Draft Guidance for Industry, Clinical Laboratories, and FDA Staff

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Draft Guidance for Industry, Clinical
Laboratories, and FDA Staff In Vitro
Diagnostic Multivariate Index Assays
ACLA Audioconference August 14, 2007
Courtney C. Harper, Ph.D. Office of In Vitro
Diagnostic Device Evaluation and Safety FDA/CDRH
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IVDMIA Guidance
July 26, 2007 FDA published a revised draft
guidance addressing the definition and regulatory
status of a small, specialized class of IVDs
referred to as In Vitro Diagnostic Multivariate
Index Assays (IVDMIAs)
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IVDMIAs
"The Black Box"
?
Rules-based Decision Tool
Diagnostic Score
"...something the end user can't understand."
Multiple Tests/Results including demographics or
other clinical parameters
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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.)
• Currently no independent review of data sets or
  clinical claims
• In contrast to many other IVDs, ordering
  physicians cannot adequately and independently
  evaluate the value and limitations of the test
  results
• Rigor in establishing analytical and clinical
  performance varies greatly among labs that
  develop IVDMIAs
• Some IVDMIAs offered for clinical use while still
  in a research phase without informed consent or
  IRB review
• Currently no mechanism for adverse event
  reporting or recalls

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IVDMIA Guidance

• Therefore, FDA believes there is a need to
  regulate these devices to ensure that IVDMIAs are
  safe and effective for their intended uses.
• With this draft guidance document, FDA seeks to
• Identify IVDMIAs as a niche, discrete category of
  devices, and
• Clarify that, even when offered as LDTs, IVDMIAs
  must meet pre- and post-market device
  requirements under the Act

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IVDMIA Guidance Background

• Original draft guidance published September 7,
  2006
• Public Meeting held February 8, 2007
• Comment period for the original draft ended March
  5, 2007
• FDA received more than 60 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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Comments

• General
• Appreciation of extended comment period and
  public meeting
• Need for clearer definition of terms
• Need for clarification of FDA regulatory process
• In favor
• IVDMIAs should be regulated by FDA
• FDA approach too narrow and piecemeal call for
  regulation of all LDTs
• FDA approach fails to address non-parity in
  regulatory pathways
• Opposed
• Concern over chilling of new technology for
  diagnostic use
• Endorsement of status quo (regulation using CLIA
  and FTC)
• Concern over impact on rare disease testing

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IVDMIA Guidance Revisions

• Stakeholders uniformly requested a clearer
• definition of IVDMIAs
• The revised guidance
• Clarifies the language of the definition
• Provides illustrative examples of devices that
  are and are not IVDMIAs

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IVDMIA Guidance Revisions

• Revised definition wording
• An IVDMIA is a device that
• Combines the values of multiple variables using
  an interpretation function to yield a single,
  patient-specific result (e.g., a
  classification, score, index, etc.), that
  is intended for use in the diagnosis of disease
  or other conditions, or in the cure, mitigation,
  treatment or prevention of disease, and
• Provides a result whose derivation is
  non-transparent and cannot be independently
  derived or verified by the end user.

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IVDMIA Guidance Revisions

• 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 Revisions

• 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 Revisions
Stakeholders were concerned that this new policy
would impede the development of new tests for
rare diseases FDA will continue to exercise
enforcement discretion and not require premarket
review for laboratory-developed IVDMIAs intended
for rare disease testing
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IVDMIA Guidance Revisions
Stakeholders were concerned this new policy would
chill the development of new diagnostic
technology The revised document clarifies the
flexible regulatory mechanisms that are in place
to handle the iterative nature of medical
devices Class II device modifications may
require ? no new 510(k) submission ?
Special 510(k) - 30 day review ? new
submission Class III devices modifications may
require ? 30 day PMA Supplement ?
Real-time supplement ? Other types of PMA
Supplements
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IVDMIA Guidance Revisions
Stakeholders requested that FDA implement a
transition period for regulatory compliance

• To provide sufficient time for IVDMIA
  manufacturers to come into compliance, FDA will
  exercise enforcement discretion for currently
  marketed, laboratory-developed IVDMIAs during an
  initial transition period.
• 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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IVDMIA Guidance Revisions

• Stakeholders requested that FDA clarify how labs
  can implement FDAs QS Regulation
• The revised guidance clarifies that FDA intends
  to issue guidance to assist laboratories that
  manufacture IVDMIAs in complying with the QS
  regulation. Until such a final guidance is
  published
• 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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IVDMIA Guidance Revisions

• Stakeholders requested that FDA clarify its
  regulatory process and labeling
• Appendix created to provide clarity on labeling
  and
• regulation of devices
• Registration and listing
• Premarket notification 510(k)
• de novo classification
• Premarket Approval PMA
• Device modifications
• Labeling

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IVDMIA Guidance Revisions

• Stakeholders requested that FDA clarify
• postmarket requirements
• Revised guidance provides additional clarity in
  this area
• User facilities malfunction/adverse event
  reporting requirements
• 21 CFR 830.30(a)
• Manufacturers malfunction/adverse event reporting
  requirements
• 21 CFR 830.50(a)
• Laboratories that manufacture IVDMIAs should
  follow the manufacturer MDR requirements for
  their IVDMIA device(s)

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Summary

• IVDMIAs will be regulated in the same manner as
  all other medical devices
• Classification and review of IVDMIAs will be
  risk-based by intended use - opportunity for
  Class I, II, and III indications

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Summary

• FDA regulation of IVDMIAs will provide
• Independent assessment of data and labeling
• - Informed by evaluation standards
• - Grounded by least burdensome mandate
• Adverse event reporting and Recalls
• Good Science is Good Science
• ( If the test is already being used on patients,
  shouldnt data already exist to show it is safe
  and effective? )

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Comments

• The comment period for this new version of the
  draft guidance ends
• August 27, 2007
• Please submit specific, constructive comments to
  the docket for FDA consideration
• http//www.accessdata.fda.gov/scripts/oc/dockets/c
  omments/getDocketInfo.cfm?EC_DOCUMENT_ID1668SORT
  MAXROWS15START1CIDAGENCYFDA

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Questions?

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

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