510k Submission Process

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510(k) Submission Process Review Considerations
Copenhagen, Denmark November 3, 2009 Kennon P.
Daniels, Ph.D. Medical Affairs Associate
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Topics for Discussion

• Introduction
• Substantial Equivalence
• Intended Use
• Predicate Devices
• Technology and Use of Data
• Safety and Efficacy Questions
• Review Process
• Review Considerations
• How to Negotiate the Review and Approval of the
  Submission
• Important Considerations when Modifying a 510(k)
  Assay

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Introduction

• Premarket Notification 510(k)
• Submission made to FDA to demonstrate that the
  device to be marketed is at least as safe and
  effective, that is, substantially equivalent
  (SE), to a legally marketed device (21 CFR
  807.92(a)(3)) that is not subject to PMA. The
  legally marketed device may be one of the
  following
• a device that was legally marketed prior to May
  28, 1976 (pre-amendments device), for which a PMA
  is not required, or
• a device which has been reclassified from Class
  III to Class II or I, or
• a device which has been found SE through the
  510(k) process. 
• There is no 510(k) form 21 CFR 807 subpart e
• Guidance for Industry and FDA Staff Format for
  Traditional and Abbreviated 510(k)s
• http//www.fda.gov/downloads/MedicalDevices/Device
  RegulationandGuidance/GuidanceDocuments/ucm084396.
  pdf

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Substantial Equivalence

• Definition
• A device is substantially equivalent if, in
  comparison to a predicate it
• has the same intended use and technological
  characteristics or
• has the same intended use as the predicate and
  different technological characteristics and the
  information submitted to FDA
• does not raise new questions of safety and
  effectiveness and
• demonstrates that the device is at least as safe
  and effective as the legally marketed device.

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Intended Use

• The Intended Use is the driving force of the
  review of the 510(k) Submission and should
  clearly state all of the following
  specifications
• Analyte measured
• Purpose for measurement
• Intended Population
• Indication for use
• Qualitative vs. Quantitative
• Testing Matrix
• Adjunctive or stand alone test

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Predicate Devices

• Search/Review
• 510(k) database using the following (one at a
  time)
• Name(s) of similar device(s) - marketed trade
  name
• Manufacturer(s) of the similar device(s)
• Analyte detected by the assay
• Analyte and Technology
• Classification Product Code
• Target claim
• Select
• Based on the intended use, technology, and data.
• The most recently cleared device under 510(k) as
  the predicate.
• Evaluate
• The 510(k) Summary of selected predicate device
  to ensure the data align.
• Determine which division of OIVD will review the
  submission based in the intended use.

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http//www.fda.gov/downloads/MedicalDevices/Device
RegulationandGuidance/GuidanceDocuments/UCM081395.
pdf
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Technology and Use of Data

• Reference the Guidances for Industry and Staff
  and the applicable federal regulations.
• Consider all components of the device
• Assay with or without sample preparation
• Multiple matrices or collection methods
• Appropriate internal and external calibrator or
  controls
• Example Nucleic Acid Amplification Testing
  (NAAT) requires internal, positive, blank, and
  negative controls
• Software off the shelf
• Instrumentation/platform assays must be
  validated for each
• Reagents for serological assays vs. nucleic acid
  assays

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Technology and Use of Data (cont)

• Considerations for the Analytical Studies
• Precision/Reproducibility (3 sites)
• 5 days, multiple operators, 2 runs/day, 3
  replicates/run, panel with 3-6 members
  (Microbiology)
• Panel that covers all genotypes/tumor types
  (Immunology/Chemistry)
• Linearity and assay reportable range
• Traceability, Stability
• Analytical Sensitivity - LOB/LOD/LOQ
• Expressed as TCID50, PFU/mL, or CFU/mL
  (Microbiology)
• Lowest and highest concentration of nucleic acid
  that will produce consistently accurate results
  for all sample types (Immunology/Chemistry)

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Technology and Use of Data (cont)

• Additional Considerations for the Analytical
  Studies
• Analytical specificity
• Assay cut-off
• Cross-contamination and carry-over
• Multi-sample format (96 well plates)
• Automated liquid handlers (sample and reagent)
• Interference and cross-reactivity
• Identify the types of substances or organisms
  that may likely cross-react or cause a false
  reaction.
• For a multiplex assay, determine if
  cross-hybridization will be a problem.
• Hemolysis, lipemia, icteris

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Technology and Use of Data (cont)

• Clinical Studies
• Reference Method Gold Standard
• Culture (Microbiology)
• Bi-directional Sequencing for genotyping
  (Immunology/Chemistry)
• Clinical diagnosis for tissue expression analysis
  (Immunology/Chemistry)
• Statistical Analysis Plan
• Matrix Comparison Study
• e.g. serum, type of plasma, type of swab

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Technology and Use of Data (cont)

• Method Comparison Study
• Types of samples
• Clinical vs. cell lines vs. plasmids
• Retrospective samples vs. prospectively collected
  samples
• Sample size
• Panel components
• Genotypes, subtypes
• Comparator method
• Clinical Diagnosis
• Bi-directional sequencing

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Technology and Use of Data (cont)

• If the IVD device labeling references an RUO
  instrument/reagent that is manufactured by a
  different company as needed but not provided
  within the IVD to conduct the test, there are two
  approaches
• IVD manufacturer redesigns the IVD device to run
  with an FDA cleared instrument or reagents.
• FDA clears RUO instrument/reagent as part of the
  IVD either
• IVD manufacturer seeks FDA clearance of the RUO
  and takes responsibility for them under own
  Quality system or
• RUO manufacturer seeks FDA clearance of RUO and
  takes responsibility for manufacturing under a
  Quality System.

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Safety and Efficacy Questions

• Safety
• Risk of misdiagnosis for the patient due to a
  false positive or false negative result
• False positives determined by studies of
  cross-reactivity, carryover and contamination,
  and duration of marker after the condition of
  interest is resolved.
• False negative results evaluated by LOD/LOQ
  Matrix effects (inhibition) and spectrum bias.

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Safety and Efficacy Questions (cont)

• Effectiveness
• Assess the analytical and clinical sample
  performance characteristics of the new device
  compared to the predicate, including
• the bias, accuracy or agreement of the new device
  compared to the predicate device
• the precision of the new device and
• the analytical specificity and sensitivity.
• Evaluate the directions for use
• Assess the warnings against unsafe use

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Review Process

• The SE determination is made based on the
  information submitted to the FDA, within 90 FDA
  review days.
• If there are unaddressed scientific issues, the
  review scientists put the submission temporarily
  on hold while the additional information is
  gathered and submitted to the FDA by the Sponsor.
• Sponsor has 30 days to submit the additional
  information requested by the FDA and may extend
  this time period to 180 days (maximum).

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Review Considerations

• Include the raw data send electronically.
• Do not submit the 510(k) submission if any of the
  following has occurred
• All of the clinical trial sites have not been
  monitored and audited.
• The Device has known performance issues.
• If the lot number of the predicate used in your
  studies was recalled.

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Review Considerations (cont)

• Avoid delays due to the Quality of the Submission
• Clear device and study descriptions
• Use of intended use samples and test conditions
• Evaluation of all matrices for which the test is
  intended
• Appropriate statistical analyses
• Clear results presentation
• Organize the 510(k) submission - use a Table of
  Contents
• Make certain the entire submission (text,
  figures, tables) is clear, consistent, and
  accurate
• Proofread and perform an internal QC of the
  document
• Ensure there are no missing documents (IRB
  approval letters, IC, financial disclosure forms,
  etc)

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Review Considerations (cont)

• Use the Screening Checklist for
  Traditional/Abbreviated Premarket Notification
  Submissions
• http//www.fda.gov/MedicalDevices/DeviceRegulation
  andGuidance/HowtoMarketYourDevice/PremarketSubmiss
  ions/PremarketNotification510k/ucm071360.htm
• Be aware of possible pitfalls for your technology
  and address them. Do not ignore impending
  problems.
• For example in DNA based tests, if you use
  someone elses extraction method, include this
  step and validate the extraction methodology with
  the new device in the submission (precision
  studies).
• Use clinical samples through all pre-analytical
  and analytical steps.

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Review Considerations (cont)

• Do not submit a device with an RUO component.
• RUO instruments/reagents are labeled as for
  research use only, not for use in diagnostic
  procedures.
• No assurance of safety and effectiveness
  regarding the test result.
• These devices are not reviewed by the FDA,
  manufactured under Quality System Regulation,
  subjected to medical device reporting,
  registered, and listed.

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Negotiating the Review and Approval

• The best Regulatory Strategy for efficient review
  by the FDA is to use the Pre-IDE Meeting Process.
  
• Tool to vet the protocol prior to commencing the
  clinical trial.
• Results in a well-prepared submission.
• Shorten the review time by the FDA for 510(k).
• Open communication through early collaboration.

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Important Considerations when modifying a 510(k)
assay

• Guidance Document Deciding When to Submit a
  510(k) for a Change to an Existing Device
• Read the entire document before using flowcharts
  at the back of the Guidance.
• Understand the definitions, do not make
  assumptions
• Go all the way through the flowcharts.
• Guidance does not establish regulatory
  requirements, i.e. it does not bind the FDA or
  industry.
• Document your decision-making.
• For modification resulting from recalls, refer to
  510(k) requirements for firm-initiated recalls.
• www.fda.gov/cdrh/ode/k951.html

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Important Considerations when modifying a 510(k)
assay (cont)

• Modifications to a 510(k) assay that could
  significantly affect the safety or effectiveness
  of the device will require a new 510(k). Some
  examples include
• New Intended Use or Indication for Use
• Changes/Additions to the Intended Use or
  Indication for Use
• Change in design, materials, chemical
  composition, energy source, or manufacturing
  process
• New or change in the Fundamental Scientific
  Technology
• Change from an immunoassay to real time PCR Assay
• Change from a polyclonal antibody detection to a
  monoclonal antibody detection

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Important Considerations when modifying a 510(k)
assay (cont)

• If deemed a non-significant change, the basis for
  this decision should be documented with
  supporting data in the 510(k) holder's device
  master file.
• Examples
• Addition of a trade name with no new indication
• Additional sizes within the specifications
• Change from one traditional sterilization to
  another
• Deleting Indications for Use
• Use FDA guidance decision trees to determine if
  the change is not significant.

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Thank You!
Kennon P. Daniels, Ph.D. Medical Affairs
Associate kdaniels_at_beaufortadvisors.com
Beaufort, LLC 500 East Main Street Suite
1301 Norfolk, Virginia 23510 1 (757)
383-6000 www.beaufortCRO.com