FDA Regulation of Molecular Diagnostics

1
FDA Regulation of Molecular Diagnostics

• Steven Gutman, M.D.
• Office of In Vitro Diagnostics

2
Medical Device Amendments of 1976

• General controls
• Registration and listing
• Good manufacturing practices
• Adverse event reporting
• Premarket review

3
FDA Device Regulation

• Risk based
• Technology a factor but not determinative
• Intended use and indications for use
• Three common classes
• Class 1 low risk
• Class 2 moderate risk
• Class 3 high risk

4
FDA Birds Eye View

• Flexible regulatory process
• Malleability of premarket review
• Introduction of streamlined down- classification
• Review experience focused claims
• Maturation in scientific approaches
• The STARD
• ReMARK initiatives
• Other evidence based reports

5
Molecular Diagnostics

• Medline
• 4097 publications molecular diagnostics
• Rare variants of human hemoglobins (Spivak
  1986)
• Detection of HPV by nucleic hybridization
  (Lorincz 1987)

6
Landmarks

• DNA probe GenProbe -- Chlamydia 1987
• FISH testing Vysis Cep 8 Spectrum orange DNA
  probe 1995
• NAT testing Roche TB 1997
• Microarray Roche AmpliChip 2004
• Expression array MammaPrint 2007
• Multiplex panels (respiratory panels) Luminex
  and Prodesse -- 2008

7
Not Quite So Niche

• 58 genetic
• 82 newborn screening tests
• Several dozen infectious disease

8
Evaluation Not Quite So New

• Analytical performance
• Clinical performance
• Labeling

9
Analytical Performance

• Accuracy
• Precision
• Specificity
• Limits of detection/measurement

10
Clinical Performance

• Yardstick of truth
• Clinical sensitivity
• Clinical specificity
• Predictive values
• Payment/penalty for weaker surrogates

11
Labeling

• 809.10(b)
• Intended use
• Performance
• Limitations

12
Field of Dreams

• Class II Special Controls Guidance Document RNA
  Preanalytical Systems (RNA Collection,
  Stabilization and Purification Systems for RT-PCR
  used in Molecular Diagnostic Testing) --
  September 2005. http//www.fda.gov/cdrh/oivd/guid
  ance/1563.html
• Class II Special Controls Guidance Document
  Factor V Leiden DNA Mutation Detection Systems
  Guidance for Industry and FDA Staff March 2004.
  http//www.fda.gov/cdrh/oivd/guidance/1236.html
• Guidance for Industry and FDA Staff Class II
  Special Controls Guidance Document Quality
  Control Material for Cystic Fibrosis Nucleic Acid
  Assays January 2007. http//www.fda.gov/cdrh/oiv
  d/guidance/1614.html

13
Field of Dreams

• Nucleic Acid Based In Vitro Diagnostic Devices
  for Detection of Microbial Pathogens December
  2005.
• http//www.fda.gov/cdrh/oivd/guidance/1560.html
• Instrumentation for Clinical Multiplex Test
  Systems Class II Special Controls Guidance
  Document Guidance for Industry and FDA Staff
  March 2005. (http//www.fda.gov/cdrh/oivd/guidanc
  e/1551.pdf) http//www.fda.gov/cdrh/oivd/guidance/
  1546.html
• Guidance for Industry and FDA Staff Class II
  Special Controls Guidance Document Gene
  Expression Profiling Test system for Breast
  Cancer Prognosis May 2007. http//www.fda.gov/cd
  rh/oivd/guidance/1627.html

14
Field of Dreams

• Guidance on Informed Consent for In Vitro
  Diagnostic Device Studies Using Leftover Human
  Specimens that are Not Individually Identifiable
  Guidance for Sponsors, Institutional Review
  Boards, Clinical Investigators and FDA Staff
  April 2006. http//www.fda.gov/cdrh/oivd/guidance
  /1588.html
• Draft Guidance for Industry and FDA Staff
  Pharmacogenetic Tests and Genetic Tests for
  Heritable Markers February 2006.
  http//www.fda.gov/cdrh/oivd/guidance/1549.html
• Drug-Diagnostic Co-Development Concept Paper
  April 2005. http//www.fda.gov/cder/genomics/phar
  macoconceptfn.pdf

15
Field of Dreams

• Guidance for Industry and FDA Staff Statistical
  Guidance on Reporting Results from Studies
  Evaluating Diagnostic Tests March 2007.
  http//www.fda.gov/cdrh/osb/guidance/1620.html
• Multiplex panels (pending)
• OIVD Web Page. www.fda.gov/cdrh/oivd

16
Field of Dreams

• FDA IOU Co-Development Guidance
• NB Literature is replete with descriptions of
  traditional designs, design pitfalls, and
  adaptive designs
• VGDS process for discovery
• Pre-IDE process for staging of clinical studies

17
Genetic Tests

• IOM 1994
• Task Force on Genetic Testing 1997
• Secretarys Advisory Committee on Genetic Testing
  2000
• Secretarys Advisory Committee on Genomics,
  Health and Society -- 2008

18
Common Regulatory Themes

• Gaps in oversight (Task Force on Genetic Testing)
  
• Clinical validity (SACGT)
• Clinical utility (SACGHS)

19
Common Regulatory Concerns

• Workload
• Iterative development
• Chilling of new technology

20
Common Regulatory Concerns

• Conflicts between CLIA/QSRs
• Appropriate review thresholds
• Off label use
• Public health

21
FDA Initiatives ASR Guidance

• ASR rule 1997
• Intent was to create with enforcement discretion
  a safe harbor for lab developed tests but with
  incremental controls
• Incremental controls on manufacturer
• Incremental controls on laboratory

22
FDA Initiatives ASR Guidance

• Misunderstanding (inadvertent or deliberate) of
  spirit and letter of law
• Q and A guidance is intended to remedy (Not
  viewed as new by FDA)

23
FDA Initiatives IVDMIA Guidance

• In Vitro Diagnostic Multivariate Index Assay
  integrative interpretative diagnostic model first
  identified in 2004
• Non-intuitive, non-transparent
• FDA did wish to withdraw enforcement discretion

24
FDA Initiatives IVDMIA Guidance

• Compliance letters
• Guidance and public meeting -- 2007
• Not viewed by FDA as new authority (dissentions
  noted) but clearly new application of authority

25
FDA Initiatives

• ASR Guidance Final
• Firms are working toward compliance
• IVDMIA Guidance under review
• Backdrop of three proposals SACGHS
  recommendations

26
Disparate Solutions

• 21st Century Personalized Medicine Coalition
  registry with comment then regulation
• ACLA registry with CMS/FDA collaborative
  regulation
• AdvaMed regulation based on risk not business
  model

27
SACGHS

• Multiple recommendations
• 200 page report
• Push toward public-private partnerships

28
Disparate Solutions

• Caveat No free lunch to do this right
  (whoever gets short straw has a day job)

29
Personalized Medicine -- good news

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

30
Personalized Medicine -- bad news

• Biology and clinical science are complex,
  nuanced, and not always intuitive
• Lack of material and method standards
• Inadequate mechanisms for data sharing
• Yelling at the test tube doesnt make the
  reaction work

31
Personalized Medicine -- growing realizations

• Sample procurement and integrity an issue
• Issues of training versus testing must be
  addressed clearly and early
• Adaptive designs are promising but represent a
  work in progress

32
Critical Path Initiative

• Biomarkers for diagnostic use
• Biomarkers for drug development
• If diagnostic drives drug treatment than the drug
  becomes hostage to the diagnostic and FDA cares

33
Predictive Marker

• Wang, ONeill, Hung, 2007
• Simon and Wang, 2006
• Pennello and Vishnuvajjala, 2005
• Sargent et al, 2005
• Pustzai and Hess, 2004

34
Predictive Marker

• Identify patients by biomarker status randomize
  therapy across all patients
• Identify patients by biomarker status randomize
  therapy in subsets
• Randomize by treatment look back at biomarkers

35
Predictive Marker
36
Wang and Simon

• Statistical magic if at first you dont succeed
• All comers trial if success blockbuster
• If failure open biomarker, bail out drug
• p penalty (split p .05)
• Blockbuster dark side halo effect good
  business, bad science

37
Predictive Marker
38
Wang and Simon

• Clear requirements
• Clear benefits
• Clear penalties left behind clinical
  sensitivity, clinical specificity, PVN, impact of
  drug on biomarker negatives
• Bad business, bad science

39
IVD Life Cycle

• Analytical Validity
• Clinical Validity
• Labeling
• Transparency
• --------------------
• Third party payers
• Users

40
IVD Life Cycle

• EGAPP http//www.egappreviews.org/workingrp/repo
  rts.htm
• Blue Cross Blue Shield Technology Assessment
• http//www.bcbs.com/betterknowledge/tec/press/
• AHRQ
• http//www.ahrq.gov/clinic/techix.htm

41
National Health Care Spending

• 1960 -- 28 billion
• 1970 -- 75 billion
• 1980 -- 255 billion
• 1990 -- 717 billion
• 2000 -- 1.36 trillion
• 2006 -- 2.16 trillion
• 2015 -- 4 trillion (20)
• 2025 25

42
RAND Health Study (2003)

• Final word on quality
• Established indicators
• Established criteria for quality
• Measured results 52 conformance
• Incorrect use of lab tests
• Potassium (22) to FOBT (72)

43
Good Science

• Dual mission to protect and promote public health
• Valuable role in translational process of new
  diagnostic tests
• Not last stop on the train

44
A.E. HousmanStars I have seen them fall,

• But when they drop and die
• No star is lost at all
• From all the star-sown sky.
• The toil of all that be
• Helps not the primal fault
• It rains into the sea
• And still the sea is salt.