US Regulatory Affairs Overview -

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					U.S. Regulatory Affairs Overview

            Copenhagen, Denmark
              November 4, 2009

        Judi Smith, MS, MT(ASCP)
          IVD/Medical Devices
                 Topics for Discussion

    •   FDA Organizational Structure
    •   Submission Pathways
    •   Terminology & Acronyms
    •   Research use only vs. Investigational use only vs. in vitro
        diagnostic products
    •   Helpful Resources
    •   Pre-IDE Meeting
    •   Investigational Device Exemptions (IDE), IDE Amendments and
    •   Pre-market Notification (510(k))
    •   Pre-market Approval (PMA)
    •   Humanitarian Device Exemption (HDE)

        FDA Organizational Structure
    • CDER - Center for Drug Evaluation and Research
          • Drugs [chemicals]
    • CBER - Center for Biologics Evaluation and Research
          • Vaccines, Therapeutics, Blood Screening Assays
    • CDRH - Center for Devices and Radiological Health
          • Medical Devices, In Vitro Diagnostics (IVD)
    • Combination product – Center based on primary mode of

    FDA Organizational Structure-
          CDRH (cont.)

            Terminology & Acronyms
    •   IDE = Investigational Device Exemption
    •   Pre-IDE = Submission prior to IDE
    •   510(k) = Premarket Notification
    •   PMA = Premarket Approval
    •   BLA = Biologics License Application
    •   HDE = Humanitarian Device Exemption
    •   IRB = Institutional Review Board
    •   BiMo = Bioresearch Monitoring
    •   SE = Substantially Equivalent
    •   CFR = Code of Federal Regulations
    •   RUO = Research Use Only
    •   IUO = Investigational Use Only
Research use only vs. Investigational use
  only vs. in vitro diagnostic products
    • Research Use
       • Clinical utility has not been determined
       • Labeled with “For Research Use Only. Not for use in
         diagnostic procedures.”
    • Investigational Use
       • Product is used for testing to support FDA submission
       • Labeled with “For Investigational Use Only. The performance
         characteristics of this product have not been established.”
    • In Vitro Diagnostic
       • Product has been cleared or approved by the FDA as
         substantially equivalent or safe and effective.
       • Labeled with “For In Vitro Diagnostic Use.”

      Submission Pathways for IVDs

    • Types of Submissions
      •   Pre-IDE
      •   IDE
      •   Pre Market Approval (PMA)
      •   Pre Market Notification (510(k)):
          •   Traditional 510(k)/de novo 510(k)
          •   Special 510(k)
          •   Abbreviated 510(k)
          •   Exempt from 510(k)
      • Biologics License Application (BLA)
      • Combination Product
      • Humanitarian Device Exemption (HDE)
                   Helpful Resources
    • What type of submission is needed to legally market
      your device in the US?

    • Type of submission is based on Product Code, product
      Class, regulatory classification number, and risk to
       • Class I, II, or III product – classified based on risk
       • Code of Federal Regulations Title 21 Parts:
          • 862, 864, 866 – IVDs
           • 868, 870, 872, 874,876, 878, 880, 882, 884, 886, 888, 890,892 –
             Medical Devices

                 Helpful Resources

    • FDA Guidances for Industry and Staff

    • Code of Federal Regulations Title 21 (21 CFR)

    • FDA databases

    • Division of Small Manufacturers Assistance

     Helpful Resources (cont.)

              Pre-Market Activities

     • FDA review of protocol – Pre-IDE
     • FDA Approval to start clinical trials –
       Investigational Device Exemption (IDE) or
     • Clinical Trials – Institutional Review Board


     • Non-binding feedback from FDA on clinical trial
       and/or regulatory pathway questions
     • Product information and protocol review by FDA
       prior to beginning studies
     • Typical 45-60 day response time
     • No User fee

     • 21CFR812
     • IDE enables sponsor to enter the device into interstate
       commerce and conduct human clinical studies
     • IDE must be approved by IRB or by FDA and IRB for
       significant risk devices
     • Most IVDs are exempt from IDE 21CFR812.2(c)(3)
     • IDE Amendments – submitted in response to FDA
       questions during IDE review
     • IDE Supplements – submitted after IDE approval, when
       there are important changes to the clinical trial

       PreMarket Notification – 510(k)

     • 21CFR807(e)
     • Pertains to section 510(k) of the Medical Device
       Amendments (1976) of the Food Drug and
       Cosmetic (FD&C) Act
     • Most Class II devices introduced into commercial
       distribution after May 28, 1976 require 510(k)
     • Pre-amendment devices on the market prior to
       May 28, 1976 are grandfathered

       PreMarket Notification – 510(k)

     • FDA Clearance
     • Types
       •   Traditional 510(k)
       •   Abbreviated 510(k)
       •   de novo 510(k)
       •   Special 510(k)
     • Exempt from 510(k) - Most Class I devices are
       exempt from 510(k) submission
       • Check FDA database

      Traditional or Abbreviated 510(k)
     • Device is Substantially Equivalent (SE) to
       another 510(k) device (predicate) already
       marketed in US
       • Same technological characteristics
       • Different technological characteristics but raises no
         new or different questions regarding SE
       • Same intended use as predicate
     • Abbreviated - Alternative to traditional 510(k)
       when guidance document exists that provides
       reasonable assurance that the device’s safety
       and effectiveness have been established

      Traditional or Abbreviated 510(k)
     • Clearance timing: 90 FDA review days
     • FDA may place submission on hold, while company
       gathers information in response to FDA questions.
     • HOLD requires response in 30 days and stops the clock
              • Withdraw,
              • Request for extension – up to 180 days,
              • Respond, or
              • Abandon
     • Clock resumes when response is submitted

                      De Novo 510(k)
     • Used when there is no predicate device but the device is
       a low risk
     • FDA must agree to this pathway prior to submission
     • De Novo 510(k) process:
        • FDA performs full review, but issues “Not Substantially
          Equivalent” determination.
        • Sponsor submits a Request for Classification.
        • FDA reclassifies the device, prepares Special Controls (if
          needed), then issues a “Substantially Equivalent” determination.
     • FDA review timing: 90 FDA review days
     • FDA reclassification and clearance: 60 FDA days

Special 510(k) - Device Modification
     • Option when device modification does not affect its
       intended use or alter the device's fundamental scientific
       • Design Change data and specifications summarized in submission
       • Raw data not included in submission
     • FDA Guidances
        • “Deciding When to Submit a 510(k) for a Change to an Existing
        • “The New 510(k) – Paradigm Alternate Approaches to
          Demonstrating Substantial Equivalence in Premarket
     • Clearance timing:
       • 30 FDA review days


     • 21CFR814

     • Class III devices
       • Defined in product-specific regulatory classification
       • Automatic Class III device if no regulatory
       • Devices not on the market prior to May 28, 1976
       • Pre-1976 devices if FDA calls for PMA

                               PMA (cont.)
     • Types of new PMA Applications:
          • Traditional - all information and data submitted together
          • Modular – information submitted sequentially grouped in “Modules”
          • Product Development Protocol (PDP) - For well-established products.
            Information, clinical trials plan, and clinical trials acceptance criteria
            submitted together
     • PMA Amendment – during FDA review of PMA
          •   Adds information or modifies a pending application
          •   Resets 180 day clock
          •   Includes additional information – voluntary or requested by FDA
     •   PMA Supplement – after PMA approval
          •   To obtain FDA approval of product changes after original PMA
     •   21CFR 814.20 – 814.39

Biological License Application (BLA)

     • Submitted to CBER
     • Blood Donor Screening – HIV, Hepatitis, etc.
     • 21CFR601
     • CBER recommends consultation with the center
       prior to submitting
     • Review similar to drugs
     • Approval Timing
         • 6 FDA review months for products of priority rating
         • 10 FDA review months for products of standard

     Humanitarian Use Devices (HUD)

        21 CFR 814.3(n):
          “Medical device intended to benefit patients in the
           treatment or diagnosis of a disease or condition that
           affects or is manifested in fewer than 4,000 individuals
           in the United States per year.”

      Humanitarian Device Exemption (HDE) is an application
      similar to PMA application, but exempt from clinical trial
      effectiveness requirements.

      FDA approval of HDE authorizes marketing of HUD.

             Combination Products

     • Example: H. pylori Breath Test, drug-eluting
       stent, bandage containing antibiotic

     • Center that reviews is based on the primary
       mode of action of the device.


     Thank You!

     Judi Smith, MS, MT(ASCP)
         IVD/Medical Devices
            Beaufort, LLC

     Association of Medical Device
        Manufacturers (AMDM)

          Beaufort, LLC
        500 East Main Street
             Suite 1301
       Norfolk, Virginia 23510
         +1 (757) 383-6000