Title: Biomarkers and FDA Regulation of In Vitro Diagnostic Devices
1Biomarkers and FDA Regulation of In Vitro
Diagnostic Devices
HUPO 2008 Amsterdam, NL 19 August 2008
Robert L. Becker Jr, MD, PhD Office of In Vitro
Diagnostics CDRH / FDA
2Biomarker Qualification
- Qualification of a biomarker means developing the
correlative information that lets us understand
its clinical meaning in a given situation - Qualification often must begin with an initial
stage of standardization of the technology, i.e.,
need for a reproducible, quantitative test.
3Once a biomarker is qualified
- Development and use of a diagnostic test
- Validation of biomarker assay
-gt OIVD (Office of In Vitro Diagnostic Device
Evaluation and Safety) clearance or approval
of diagnostic tests that measure biomarkers in a
clinical setting
4Outline
- Risk-based classification and submission paths
- Validation of Biomarker Assay (for an Intended
Use) submission elements - Analytical Validation
- Clinical Validation
- Sources for Help
5Regulatory Mechanisms for IVD Markers
- PMA
- 510(k)
- De novo
- IDE
- HDE
Risk-Based Regulation
6Risk-Based Classification of IVDs
- Class III most complex, high risk
- e.g. cancer diagnosis or screening
- Premarket Application PMA
- Safety, effectiveness
- Class II more complex, moderate risk
- e.g. prognosis, monitoring in already diagnosed
cancer patients - Premarket Notification 510(k)
- Substantial equivalence
- Special controls
- Class I common, low risk devices
- Most exempt from premarket submission
- General controls
7Risk for Intended Use determines type of
submission
- A CFTR genotyping assay with the indication
- For carrier screening
- For fetal screening
- One multiplex instrument system with two devices
- Device detecting BCR-ABL for CML diagnosis
- Device detecting BCR-ABL for monitoring
? 510(k) ? PMA
8In-Vitro Diagnostic Products
Review and Approval Requires
- Evidence for Safety
- Are there reasonable assurances, based on valid
scientific evidence that the probable benefits to
health from use of the device outweigh any
probable risks? 860.7(d)(1) - Evidence for Effectiveness
- Is there reasonable assurance based on valid
scientific evidence that the use of the device in
the target population will provide clinically
significant results? 860.7(e)(1)
Ultimately - provide patients access to new and
useful diagnostic tests
9Major Elements of IVD Submission
- Intended use/indications for use
- Device description
- Analytical Validation
- Clinical Validation/Clinical Utility
- Instrument and software validation, if applicable
- Labeling (package insert) - truth in labeling
- For PMA - manufacturing, design controls, quality
system requirements (QSR/GMP) (21 CFR 820 all
products must follow)
10Intended Use
What assay measures, how to use
results determines FDA classification, risk
Review path, types of studies depend on IU
claims Independent of the technology or assay
format. Example MammaPrint is a qualitative
in vitro diagnostic test service, performed in a
single laboratory, using the gene expression
profile of fresh frozen breast cancer tissue
samples to assess a patients' risk for distant
metastasis. The test is performed for breast
cancer patients who are less than 61 years old,
with Stage I or Stage II disease, with tumor size
lt 5.0 cm and who are lymph node negative. The
MammaPrint result is indicated for use by
physicians as a prognostic marker only, along
with other clinicopathological factors.
Analyte
Indication For Use
11Analytical Validation
- Analytical performance
- Precision (repeatability, reproducibility)
- Accuracy
- Sensitivity, Limit of Detection
- Specificity (interference, cross-reactivity)
- Sample type / matrix
- Sample preparation / conditions
- Performance around the cut-off
- Potential for carryover, cross-hybridization
12Analytical Validation Steps
- Varies with technology
- Varies with Quantitative or Qualitative
- Varies with setting of use (e.g., marketed vs.
single laboratory service) - Varies by what is reported (individual markers
vs. composite score)
13For example Precision
- Intended to capture total test variability
(should capture all steps from specimen prep to
final result) - Varies with technology, setting of use, and what
is reported - Day to day variation
- Lot to lot variation
- Operator to operator variation
- Lab to lab variation (Depends)
- For each marker or the final score (Depends..)
14Accuracy
- Real clinical samples
- Compare to a reference method, e.g.,
bi-directional DNA sequencing for genotyping - Certain assays comparison of assay results to a
clinical outcome
Analytical validitydoes my test measure the
analyte I think it does? Correctly? Reliably?
Clinical validitydoes my test result correlate
with the expected clinical presentation? How
reliably?
15Limit of Detection
- Index derived from microarray
- assess specimen integrity and minimum
amount of RNA to run assay - Combines results of multiple assays
- May need to establish LOD for each assay to
determine if it is reasonable - FDA refers to several CLSI guidance documents
(EP5, EP6, EP9, EP12, EP17)
16Instrument
- Performance characteristics described in the
Special Controls Guidance document
Instrumentation for clinical multiplex test
systems. - http//www.fda.gov/cdrh/oivd/guidance/1546.html
17Software
- Software documentation for a software controlled
medical device of moderate level of concern per
FDAs Guidance for the Content of Premarket
Submissions for Software Contained in Medical
Devices http//www.fda.gov/cdrh/ode/guidance/337.h
tml - Software Risk assessment Ensuring that all
potential hazards are identified, e.g., incorrect
results/interpretation. Documenting how these
hazards are reduced or mitigated by the test
design.
18Clinical Validation Steps
- Training Set(s)
- Develop classifier and/or cut-offs
- Fully specified device
- Test Set (s)
- Independent Validation on intended use population
-
19Statistical challenges
- Prospective studies are not always feasible
- Retrospective and / or banked samples are a
challenge - Need to be representative of intended use
population - Consecutive cases meeting a set of inclusion /
exclusion criteria - Storage conditions dont impact assay
20Appropriate Statistical Methods
- Well planned studies
- Confirmatory studies w/Protocols
- Fully specified device, hypotheses, success
criteria, statistical methods - Statistical Guidance on Reporting Results from
Studies Evaluating Diagnostic Tests (March 07)
http//www.fda.gov/cdrh/osb/guidance
/1620.pdf
21Labeling of In Vitro Devices
- 21 CFR 809.10
- Clear instructions for use
- Need to capture expected analytical and clinical
performance of device - Prospective performance in intended use
population
22Some tips
- Study plan for an in vitro diagnostic product
depends on the intended use - Type of data required depends on the intended
use, indications for use, technological
characteristics of the device, and on other
claims made by the manufacturer
23Device Advice
- See the Center for Devices and Radiological
Health website at http//www.fda.gov/cdrh, and
especially its Device Advice link at
http//www.fda.gov/cdrh/devadvice, for useful
information about the regulation and review of
medical devices, including in vitro diagnostic
devices.
24Additional Guidance Documents
- Pharmacogenetic tests and genetic tests for
heritable markers - http//www.fda.gov/cdrh/oivd/guidance/1549.pdf
- Quality Control Material for Cystic Fibrosis
Nucleic Acid Assays - Class II Special Controls
Guidance Document http//www.fda.gov/cd
rh/oivd/guidance/1614.pdf - Drug-Diagnostic Co-Development Concept Paper
http//www.fda.gov/cder/genomics/pharmacoconceptfn
.pdf - Guidance on Informed Consent for In Vitro
Diagnostics Device Studies Using Leftover Human
Specimens that are Not Individually Identifiable
http//www.fda.gov/cdrh/oivd/guidance/1588.pdf
25Pre-IDE
- Not an IDE (just a misnomer)
- It is a protocol review and regulatory guidance
- No charge to the sponsor
- Non-binding on either party
- Recommended for novel devices / uses
- http//www.fda.gov/cdrh/oivd/presentations/042203-
Altaie.html
26Pre-IDEs
- Allow us the opportunity to become familiar with
the technology before seeing the formal
pre-market submission. - Provide manufacturers with advice on types of
submission and types of data appropriate in order
to maximize the likelihood of rapid premarket
review with a successful outcome.
27Acknowledgements
- Special Thanks to
- Dr. Reena Philip
- Dr. Maria Chan
- Dr. Estelle Russek-Cohen
- Dr. Zivana Tezak
28Thank You !
- RobertL.Becker_at_fda.hhs.gov
- General information http//www.fda.gov/cdrh/index
.html - OIVD website http//www.fda.gov/cdrh/oivd/