1. Get Ready for FDA Oversight of Laboratory Developed Tests Presenter:
November 4, 2010
Robert Footlik, MS, MT(ASCP), HCLD(ABB)
Laboratory Compliance Officer
Cedars-Sinai Medical Center, Los Angeles, CA

2. Background on Laboratory-Developed Tests
LDTs are regulated under CLIA, as non-FDA approved tests, test kits, or test systems.
For non-FDA-approved methods, laboratories must establish and document their own test performance characteristics, as applicable, according to CLIA rules.
Now the FDA has decided to exercise its authority to regulate LDTs, but has not decided how to do it.
….Why?

3. Medical Devices and the FDA
The FDA does not regulate clinical laboratories
Since the implementation of the Medical Device Amendments of 1976, the FDA has had statutory authority to regulate all medical devices.
Medical Device: “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or similar related article. . . intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals” (FFDCA 201(h))

4. Medical Devices and the FDA
Definition of In-Vitro Diagnostic Devices (IVDs)
IVDs are a subset of medical devices which are “reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae” (21 CFR 809.3)

5. Background on Laboratory-Developed Tests
Enforcement Discretion:
When FDA does not enforce some or all applicable laws and regulations on certain categories of products (drugs, devices, biologics, etc.)
Enforcement discretion not unique to LDTs
Enforcement discretion does not change the fact that the law still applies
Many different reasons for this practice
(risk, history, timing, resources, etc.)
Practices like this do occur, but may change
(often because of changes in risk profile of the products)

6. Background on Laboratory-Developed Tests
“test kit” manufactured for distribution to multiple labs
Test designed, manufactured, and used in a single lab
FDA
“enforcement discretion”
FDA approval
LDTs (lab developed tests)
enter the market without review
Patient
“Test kits” distributed to patients, hospital, or clinical lab
1) Commercially Distributed Test Pathway:
2) Lab Developed Test (LDT) Pathway:

7. Risk-Based Classification of IVDs: Intended Use
IVD Classification
Risk-Based Classification of IVDs: Intended Use
The classification of an IVD by the FDA is risk-based, and determined based upon the intended use of the device
Intended Use:
General description of the disease or condition that the device will diagnose, treat, prevent cure or mitigate
Defines the patient population
Defines specific type of specimen
A single IVD can have multiple intended uses

8. Risk-Based Classification of IVDs
The risk of an IVD is based on the consequences of a false result
3 Classification levels
Class I: common, low risk devices
Class II: more complex, moderate risk
Class III: most complex, high risk and novel intended uses

9. Risk-Based Classification of IVDs
IVDs: Classification Breakdown

10. Clinical Laboratory Improvement Amendments of 1988 (CLIA)
Implemented increased oversight of laboratory testing:
Certification process
Accreditation requirements
Periodic inspections
Education and training requirements
Proficiency testing

11. Clinical Laboratory Improvement Amendments of 1988 (CLIA)
FDA: Focus of CLIA is on the quality of the lab performing the tests, not on the tests themselves
CLIA regulation of labs and FDA regulation of tests are complementary for diagnostic testing

12. FDA
CMS (CLIA)
Registration/Listing
Registration of establishment
Publicly available listing of marketed tests
Registration and certification of Lab
Lists of tests maintained by CMS (not currently publicly accessible)
Analytical validation
Premarket review of analytical data for Class II and Class III tests
Sampling after marketing during periodic laboratory inspections
Clinical validation
Premarket review of clinical claims for Class II and Class III tests;
Postmarket surveillance of clinical claims for Class I tests
Not required
Quality System
GMPs, QS Regulations
Assessed by inspection
Laboratory Quality system
Design Controls
Required for Class II and Class III tests and all other devices with software
Not required.
Software not addressed by CLIA.
Adverse Event Reporting
Yes No
Postmarket surveillance
Recalls

13. Potential Risks of Insufficient Oversight As Seen by the FDA
Tests without sufficient oversight can lead to incorrect diagnoses.
FDA has observed the following in LDTs in recent years:
Faulty data analysis
Exaggerated clinical claims
Fraudulent data
Lack of traceability/change control
Poor clinical study design
Unacceptable clinical performance

14. Current Landscape
Secretary’s Committee on Genetics, Health, and Society (SACGHS) – Released Recommendations of Genetic Testing Oversight - Recommended that that FDA address all lab tests using risk based approach (2008)
Agency for Healthcare Research and Quality (AHRQ) – Published a draft Technology Assessment on Quality, Regulation and Clinical Utility of Laboratory-developed Tests (2010)
Congressional Interest
Diagnostic Test Oversight
Personalized Medicine
DTC testing

15. Current Landscape Move toward Personalized Medicine
Increased use of lab tests in clinical care
Companion diagnostics increasingly developed – different risks
New Business Models
LDT viewed as ‘easier’ route to market
Driving venture capital funding decisions

16. What Action Should the FDA Take?
The FDA convened a public meeting on the oversight of LDTs at the University of Maryland, held on July 19-20, 2010.
Approximately 700 stakeholders, including laboratory professionals, clinicians, and industry representatives were in attendance.
Series of public presentations and panel discussions on patient and clinical considerations concerning LDT oversight, clinical laboratory challenges, direct-to-consumer testing, and education and outreach.

17. What Action Should the FDA Take?
The FDA’s Expressed Position:
New era of molecular diagnostics and personalized medicine
Broad agreement that diagnostics are the focus of personalized care
Public needs assurances that diagnostics are sound and reliable

18. What Action Should the FDA Take?
FDA Mission
Benefits
Risks
Getting safe and effective devices to market as quickly as possible. . .
While ensuring that current devices on the market remain safe and effective. .

19. Personal Observations/Comments
CLIA regulations are not well understood by many stakeholders. There is no such thing as a moderate complexity LDT.
LDTs are for single lab use only, and compliance with FDA labeling rules for manufacturers that develop IVDs for sale and general distribution to many labs should not apply.
For LDTs, FDA risk-based classification only addresses half the equation. The FDA must perform a true risk/benefit analysis, as the benefit may outweigh the risk.
Genetics is not a laboratory specialty under CLIA, so there are no specific requirements for genetic testing. Only the specialty of clinical cytogenetics has been defined with rules under CLIA. Clinical cytogenetics should be a subspecialty of genetics under CLIA, and CMS needs to address this problem.
FDA should require disclaimer similar to that for use of ASRs when labs report results of non-FDA approved tests.
There is a disconnect between FDA's concern to protect the public re: use of LDTs and the FDA's categorization of many tests as waived from CLIA requirements.

20. FDA Action
The FDA said that it would review comments from the meeting, as well as those submitted to the federal docket by Aug. 15, and develop a draft oversight framework for public comment “with the goal of providing a level of predictability as quickly as possible.”