Laboratory Developed Tests whats brewing at FDA

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Laboratory Developed Tests whats brewing at FDA

• Steven Gutman, M.D.

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Medical Device Amendments of 1976 General
Controls

• Registration and listing
• Good manufacturing practices
• Post market reporting

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Premarket Review

• 510(k)
• PMA
• Administrative differences
• Core science the same

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Well Defined Interests

• Analytical performance
• Clinical performance
• Labeling adequate instructions for use
• FDA work processes quite transparent

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Regulatory Scheme Launched

• Regulations
• Classification
• Procedures for review practice
• Guidances

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Applied to Commercial Kits

• Not directed at laboratory developed devices
  (also known as in house tests, laboratory test
  services, home brew tests)
• Enforcement discretion

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Laboratory Developed Tests

• Historic practice
• Broad menu

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Laboratory Developed Tests

• Subject to CLIA
• Analytical performance
• Quality system

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Laboratory Developed Tests

• No threshold between research and clinical use
• No specific premarket review (post hoc sampling)
• No clinical validation (not prohibited but not
  required by CLIA)
• No reporting requirements

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ASR Rule -- 1997

• Incremental increase regulation
• Down-classification
• Deliberate effort to create safe harbor

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Unique Backdrop

• Widespread promulgation of RUO/IUO devices for
  clinical use
• Explosive market in lab developed tests
• Evolving CLIA program
• Increase attention to genetic testing -- human
  genome project

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Regulation of Genetic Tests

• Hot Button Item
• IOM -- 1994
• Task Force on Genetic Testing -- 1997

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Analyte Specific Reagents

• Antibodies, specific receptor proteins, nucleic
  acid sequences, and similar biological reagents
  which through chemical binding or reaction with
  substances in specimen are intended for
  identification and quantification of an
  individual chemical substance or ligand in
  biological specimens

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ASR Impact on Manufacturers

• Required to register and list
• Required to meet good manufacturing practices
• Required to report adverse events
• Restricted distribution, use, and labeling

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ASR Impact on Laboratories

• Restricted to high complexity laboratories
• CLIA requirements
• Report disclaimers

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Labeling of ASRs

• Mandatory language, restricted labeling
• Discretionary explanation

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ASR Exceptions

• HIV testing
• TB testing
• -------------
• Genetics testing
• Microarray testing

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Abuse of ASR Rule

• Inadvertent or deliberate use of rule to avoid
  premarket review

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SACGT -- 2000

• CLIA role expanded
• CDC post-market data gathering
• FDA review new tests

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SACGT

• Risk based
• New regulatory models
• Light touch
• Emphasis on truth in labeling

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SACGT

• Risk based approaches failed
• Template hit fertile soil
• Committee dissolved
• Recommendations on hold

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Persistent Interest

• Industry seeking parity IVAT
• Consumer advocates seeking more comprehensive
  regulatory assurance
• Congress concerned with issues

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Congress

• Smith hearing on DTC sales of nutrigenomic tests
• Obama bill
• Kennedy bill

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SACGHS and the Oversight of Genetic Tests

• SACAGS charged on March 26 with investigating
  adequacy of oversight
• Charge broad and aimed at all sectors of the
  health care system
• Goal is improvement of health quality

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SACGHS and the Oversight of Genetic Tests

• Ambitious charge develop a comprehensive map of
  steps needed for evidence development and
  oversight of genetic and genomic tests with
  improvement of health quality as primary goal

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SACGHS and the Oversight of Genetic Tests

• Talented task force
• Andrea Ferreira-Gonzalez, chair
• 5 members of SACGHS
• Ad hoc members from laboratories, industry, and
  academia

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SACGHS and the Oversight of Genetic Tests

• Sharp timeline
• First draft of report by July 2007
• Complete project by end of 2007
• Submit a report to secretary in early 2008

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SACGHS and the Oversight of Genetic Tests

• What do clinical validity and analytical validity
  mean and what separates the two?
• What should be minimum requirements for clinical
  and analytical validity?
• What stage of test development should these be
  required? What about utility?

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SACGHS and the Oversight of Genetic Tests

• What resources are available for proficiency
  tests? What is the burden on labs to perform PT?
  How much PT is being done?
• What, if any additional oversight by CLIA would
  be beneficial? If needed what would it involve

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SACGHS and the Oversight of Genetic Tests

• What map describes the intersecting
  regulation/oversight bodies surrounding genetic
  tests?

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FDA Activities

• Two guidances
• FAQs on ASRs
• In Vitro Diagnostic Multivariate Index Assays
  (IVDMIAs)

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FAQs on ASRs

• Based on a guidance submitted by AdvaMed
• Not intended to introduce new regulatory concepts
• Intended to clarify the ASR

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Q and As on ASRs

• Spirit of the rule allows for two choices
• Tests developed, optimized, and validated by
  companies for use in labs
• Tests developed, optimized and validated by labs
  as laboratory developed tests

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Q and As on ASRs

• Spirit of the rule implied very different
  responsible bodies
• Commercial tests company under quality control
  of FDA
• Laboratory Developed tests laboratory under
  quality control of CLIA or CLIA

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Q and As on ASRs

• Core principle behind guidance is to ensure that
  companies sell labs building blocks and not
  pseudo kits for use in laboratory developed
  assays
• Complex and nuanced document

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IVDMIAs

• Signals identification of a new class of
  laboratory developed tests that FDA believes may
  not be a good fit for enforcement discretion and
  regulation under CLIA
• First test identified in 2004 FDA intention was
  quite narrow

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IVDMIAs

• Software derived (and often driven) assays which
  combine multiple signals into an index or score
• Index or score cannot be interpreted or clearly
  understood without information provided by the
  sponsor
• Represents a locked cabinet, needs a combination
  or key

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Guidances

• Subject of considerable interest
• FDA responses included extension of comment
  period for both documents and public meeting to
  obtain input on IVDMIAs

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Guidances

• Request was for concrete input and concrete
  suggestions
• Lots of comments for both documents
• En Media Res
• Timeline for further decision making uncertain

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Good News Bad News

• FDA is considering options in an area of complex
  discussion and deliberation
• FDA welcomes input

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Good News Bad News

• FDA resources are limited
• FDA review tools are sharper then ever
• FDA understands opportunity cost of delay

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Good News Bad News

• FDA not only player
• What companies like better then an FDA letter!
• Good science is good science

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Good Science

• Lot at stake
• Personalized medicine
• Impacts diagnostics
• Impacts therapeutics

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Good Science

• Right focus
• Questions wont go away