# Presentation: 218550

## Biomarkers 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**

## Biomarker 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.

**Notes:**
Not discussion qualification for such uses as “surrogate endpoint”. This is a complex area with many different stakeholders and concerns. In general, a long and somewhat ill-defined process.

## Once a biomarker is qualified

- Development and use of a diagnostic test
- Validation of biomarker assay

*-> ****OIVD**** ****(****Office of In Vitro Diagnostic Device *
*    **Evaluation and Safety****)**** – ****clearance or approval of diagnostic tests ****that measure biomarkers in a clinical setting*

## Outline

- Risk-based classification and submission paths
- Validation of Biomarker Assay (for an Intended Use) – submission elements
- Analytical Validation
- Clinical Validation
- Sources for Help

## Regulatory Mechanisms for IVD Markers

- PMA
- 510(k)
- De novo
- IDE
- HDE

*Risk-Based Regulation*

## Risk-Based Classification of IVDs

- 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*

**Risk-Based Classification of IVDs**

## 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

*Risk for Intended Use determines type of submission*

********* ******510(k)***
********* ******PMA***

***PMA ***
********* ******510(k)***

## In-Vitro Diagnostic Products

***   ******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)]*

*Review and Approval Requires*

- Ultimately - provide patients access to **new** and **useful**** **diagnostic tests

## Major 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)

## Intended Use

**       ****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 <= 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***

***What assay measures, how to use results***
***determines FDA classification, risk***

## 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

- 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

**Analytical Validation**

## Analytical 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)

## For 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..)

## Accuracy

- _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 validity—does my test measure the analyte I think it does?  Correctly?  Reliably?*

*Clinical validity—does my test result correlate with the *
*expected clinical presentation?  How reliably?*

## Limit 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*...)

## Instrument

- Performance characteristics described in the Special Controls Guidance document: Instrumentation for clinical multiplex test systems.
- http://www.fda.gov/cdrh/oivd/guidance/1546.html

## Software

- Software documentation for a software controlled medical device of moderate level of concern per FDA’s Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices http://www.fda.gov/cdrh/ode/guidance/337.html
- 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.

## Clinical Validation Steps

- Training Set(s)
- Develop classifier and/or cut-offs
- Fully specified device
- Test Set (s)
- Independent Validation on intended use population

**Notes:**
Genetic / genomic tests:

Single gene or multiplex
Genotyping 
Expression (snapshots)

Statistical issues - the number of possible test outputs affects statistical sample size; bias

Expression patterns or genetic algorithms should be developed and confirmed in at least two independent data sets - training set and validation set, respectively
Patterns or algorithms should generally be pre-specified prior to the confirmatory (validation) study

## Statistical 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 don’t impact assay

## Appropriate 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

## Labeling 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

## Some 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

## Device 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.

## Additional 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/cdrh/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

## Pre-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

## Pre-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.

## Acknowledgements

- 		Special Thanks to:
- Dr. Reena Philip
- Dr. Maria Chan
- Dr. Estelle Russek-Cohen
- Dr. Zivana Tezak

## Thank You !

- RobertL.Becker@fda.hhs.gov
- General information: http://www.fda.gov/cdrh/index.html
- OIVD website: http://www.fda.gov/cdrh/oivd/