FDA Update:

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FDA Update IVDMIAs and Molecular Testing
ACLAs 13th Annual Meeting Laboratories Rx for
the Future April 18, 2008
Courtney C. Harper, Ph.D. Office of In Vitro
Diagnostic Device Evaluation and Safety FDA/CDRH
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Agenda

• FDA Oversight of Diagnostic tests
• Current climate of genetic testing
• IVDMIA summary overview

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FDA Device Regulation

• Medical Device Amendments of 1976
• Risk based regulation
• General controls
• Special controls
• Pre-market notification or approval
• Technology a factor but not determinative
• Intended use and indications for use
• Diagnostic tests a subset of medical devices

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IVDs Unequal Regulation
CLIA
Longstanding FDA policy results in a non-level
playing field for IVD manufacturers. Distributed
Test kits must undergo FDA review prior to
marketing while lab developed tests enter the
market without review
test kit manufacturer
FDA enforcement discretion
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Current State of Affairs

• Industry seeking regulatory parity between IVDs
  and LDTs including genetic tests
• Consumer advocates seeking more comprehensive
  regulatory assurance of LDTs and genetic tests,
  and more assurance of clinical validity and
  clinical utility
• Commercial Laboratories seeking predictability,
  some favor status quo or CMS regulation over FDA
  regulation
• Congress concerned with issues
• Kennedy, Obama bills
• GAO DTC testing report

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Current State of Affairs

• Secretary Leavitt Priority
• Personalized Medicine
• SACGHS Oversight Report includes recommendations
  to
• Require more proficiency testing for genetic
  tests
• Establish a mandatory registry for genetic tests
• Have FDA address clinical validity of all
  laboratory tests
• Increase research efforts to generate clinical
  utility information for genetic tests

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FDAs Critical Path
Biomarker development and qualification is of
interest to both FDA and Industry as a way to
strengthen drug discovery programs and
personalized medicine (part FDAs Critical Path
Initiative)

• Discover new biomarkers to modernize product
  development (e.g. genetic/genomic markers)
• Requires a device to measure them

One Goal Translation of new biomarkers from
Basic Science to Clinical Use
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Advantages

• Potential Benefits of new Biomarkers
• Develop new and innovative clinical diagnostics
• Streamline drug discovery/development programs
• Identify potential responders to a specific drug
• Identify individuals at risk for adverse events

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IVDMIAs
A growing category of new biomarkers for clinical
diagnosis are In Vitro Diagnostic
Multivariate Index Assays (IVDMIAs)
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IVDMIAs
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The Promise of IVDMIAs

• New Biomarkers may lead to
• Better healthcare choices for patients
• Better drug discovery decisions for companies,
  facilitating a critical path for streamlined drug
  development

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The Risks of LDT IVDMIAs

• Most IVDMIAs are marketed with high risk
  diagnostic claims (e.g., cancer
  diagnosis/prognosis, Alzheimer's disease risk,
  Stroke, etc.)
• Clinical validity/utility often unestablished
• Currently no mechanism for adverse event
  reporting or recalls

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IVDMIA Guidance Background
FDA published a draft guidance on IVDMIAs that
defines a narrow niche of devices. The guidance
states that these devices are subject to FDA
regulation rather than enforcement discretion
even when offered as laboratory developed tests.

• FDA Concerns regarding lab developed IVDMIAs
• No independent review of data sets or clinical
  claims is it clinically valid?
• Degree of scientific rigor varies greatly among
  IVDMIA developers
• Some lab developed IVDMIAs offered for clinical
  use while still in a research phase
• Use of test information non-intuitive,
  non-transparent to well trained health care
  providers

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IVDMIA Guidance Background

• Original draft guidance published September 7,
  2006
• Public Meeting held February 8, 2007
• Revised draft issued July 26, 2007
• FDA received more than 50 comments
• Submitted primarily by IVDMIA developers,
  commercial laboratory groups, rare disease
  research advocates, consumer advocates,
  pharmaceutical companies, IVD manufacturers, 3rd
  party payers, cancer prevention groups,
  physicians, private citizens

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IVDMIA Guidance

• Examples
• Devices that would be considered IVDMIAs
• Devices classified under 21 CFR 866.6040, Gene
  expression profiling assay for breast cancer
  prognosis (e.g., Agendia MammaPrint Test
  cleared February 2007)
• A device that integrates quantitative results
  from multiple immunoassays to obtain a
  qualitative score that predicts a persons risk
  of developing a disease or condition
• A device that integrates a patients age, sex,
  and genotype of multiple genes to predict risk of
  or diagnose a disease or condition

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IVDMIA Guidance

• Devices that would not be considered IVDMIAs
• Devices that combine multiple variables into a
  single result that facilitates an interpretation
  of the variables that clinicians could otherwise
  interpret themselves because of extensive
  experience and training in use of the device
• (e.g., standard maternal Triple Screen testing)
• Genotype determination (e.g., CFTR genotyping)
• Chromosomal copy number determination
• (i.e., devices intended to identify abnormal
  gains and losses in a patients chromosomal DNA)
• Common clinical calculations
• (e.g., creatinine clearance, determination of
  cholesterol ratios, estimated glomerular
  filtration rate)
• Devices that analyze stored clinical information
  to, e.g., flag results, create disease
  registries, summarize patient-specific
  information in an integrated report, and/or track
  a patients treatment or disease outcome (e.g.,
  Clinical Decision Support tools)
• Common, public demographic risk calculations
  (e.g., Gail Index, Framingham Risk Score)

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IVDMIA Guidance

• Exceptions
• FDA will continue enforcement discretion for
  laboratory-developed IVDMIAs intended for rare
  disease testing
• Until FDA issues guidance on how labs may best
  meet FDA quality system requirements, FDA intends
  to exercise enforcement discretion with regard to
  post-market enforcement of QS requirements for
  such laboratories
• (For PMA applications, FDA will work with the
  applicant to determine
• the least burdensome approach to developing QS
  compliant systems)

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Stakeholder Concerns

• FDAs workload
• Regulatory process labs unfamiliar w/ FDA
• Iterative development of tests
• Chilling of new technology
• Perceived conflicts between CLIA/QSRs
• Appropriate review thresholds
• Off-label use
• Public health

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Disparate Proposals

• Coalition for 21st Century Medicine registry
  with comment for 3 to 5 years followed by phased
  in regulation
• ACLA CMS registration with FDA consult
• AdvaMed regulation by risk rather than business
  model

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IVDMIAs Good News

• Technology is there (reagents, hardware,
  software, design elements)
• 2003 genomic map unveiled
• Broad organizational commitment (NIH, FDA, HHS)

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IVDMIAs Bad News

• Biology and clinical science are complex,
  nuanced, and not always intuitive
• Sample procurement and integrity an issue
• Statistical methods complex - Issues of training
  versus testing must be addressed clearly and
  early
• Lack of material and method standards
• Inadequate mechanisms for data sharing

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IVDMIA Guidance

• To provide sufficient time for IVDMIA
  manufacturers to come into compliance, FDA has
  proposed an initial transition period for
  currently marketed, laboratory-developed IVDMIAs.
  
• This phased-in, 18 month transition period
  allows
• 12 months for submission of a 510(k) or PMA
• 6 months additional enforcement discretion during
  FDA review of submission

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Current Status

• Issues under review
• Decision making and timing uncertain
• SACGHS report expected to be provided to HHS in
  the near future to address broad issues of gaps
  in the area of genetic testing and possible
  mechanisms to address these

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Questions?

• courtney.harper_at_fda.hhs.gov
• 240-276-0694