1. FDA and LDT
Laurel Estabrooks, PhD, FACMG VP Genetics Business Development SCC Soft Computers

2. Timeline July 2014 – FDA notified Congress of intent
September 30th, 2014 – released documents
Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)
FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)

3. Timeline February 2, 2015 – 120 day Comment Period Closed
Had 2 day public meeting with 6 panels (80 registered to speak)
Numerous groups submitted questions and concerns
Some groups hired lawyers to address this (ACLA)
Unknown date – Final Guidance will be released
After review of all submitted comments and concerns
Responses to above questions and concerns will be provided at the time of the Final Guidance release

4. Cost FDA Regulation + Delay of Test Release =
Reaction to FDA Draft
What is the device to be regulated?
Isn’t this duplicating CLIA role?
Is this equation really valid?
Cost FDA Regulation + Delay of Test Release =
Better Health Care

5. Definition of LDT FDA Definition of an LDT
"a type of in vitro diagnostic test that is intended for clinical use and designed, manufactured and used within a single laboratory“
Prompted New Definition of an LDP
a professional service that encompasses and integrates the design, development, validation, verification, and quality systems used in laboratory testing and interpretative reporting in the context of clinical care

6. CLIA vs. FDA Intent CLIA Performance specifications for FDA
Accuracy
Precision
Analytical sensitivity
Analytical specificity
Reportable range of test results
Reference intervals
Other performance characteristics deemed required for proper test performance
FDA
Clinical validity
Ability of a diagnostic device to measure or detect the clinical condition for which the device is intended
Test (analytical) validation before marketing/release
QSR (Quality System Regulations)
Adverse event reporting
Ability to remove unsafe devices/tests

7. Demonstration of Clinical Validity
Study with patients (clinical trials, double blind studies)
Use of clinical literature
Reduce investment in clinical studies to demonstrate validity

8. QSR (Quality System Regulations)
Focus on Design Control
Design controls are procedures that test developers use to guide the development and design of their devices.

9. MDR (Medical Device Reporting)
Requires submission of reports whenever you become aware of information that reasonably suggests your LDT may have caused or contributed to a death or serious injury, or the LDT has malfunctioned and the malfunction would be likely to cause or contribute to a reportable death or serious injury should it recur

10. How many labs will be affected?
ACLA estimates
10,000 labs in US providing more than 100,000 LDT services

11. Classes of Risk - Highest
Class III
Companion Diagnostics
Tests that predict patient response to drug(s)
Asymptomatic testing/screening
Any test that already has an FDA approved equivalent test
PMA
Could take up to a year to complete process

12. What is a PMA? PMA (Pre-Market Approval): Provides FDA Approval
Includes an FDA review
May require a clinical trial
Estimated Cost ~$250K

13. Classes of Risk - Moderate
Class II
FISH
Arrays
510(k)
Could take a few months to complete process

14. What is a 510(k) ? Provides FDA Clearance
Likely to be performed by a Third Party Review
Estimated Cost ~$4K
510(k) requires demonstration of substantial equivalence (SE). SE means that the new device is as safe and effective as the predicate device(s).

15. What is a 510(k) ?
A device is SE if, in comparison to a predicate device it:
has the same intended use as the predicate device; and
has the same technological characteristics as the predicate device; or
has different technological characteristics, that do not raise new questions of safety and effectiveness, and the sponsor demonstrates that the device is as safe and effective as the legally marketed device.

16. Classes of Risk - Lowest
Class I
Rare diseases (<4,000 tests/year)
“Traditional LDT” (chromosome analysis)
Unmet need
Enforcement discretion
Notification and MDR still required

17. Continued Enforcement Discretion with Respect to Premarket Review
LDTs used for Rare Diseases
# of persons tested <4,000 (FDA now recognizes testing frequency does not equal disease frequency so may alter this)
HUD qualification (Humanitarian Use Device)/HDE (Humanitarian Device Exemption)

18. Continued Enforcement Discretion with Respect to Premarket Review
Traditional LDTs
If available when FDA began enforcement discretion in 1976
Interpretation by lab professionals, no automated instruments or software for interpretation
LDTs for unmet needs when no FDA-cleared or approved alternative exists

19. Enforcement Discretion in Full
Enforcement Discretion – FDA will choose not to regulate at this time
LDTs used for forensic purposes
LDTs used in CLIA-certified, high complexity laboratories for transplantation

20. What about “tweaking”?
When a clinical lab alters a test in a way that can change its
Intended use
Performance
For example: altering specimen type or target population
Then the lab is subject to Premarket Requirements

21. Other considerations Intended Use Clinical Validity
Dr. orders a test that is not intended for patient’s condition
Test identifies something “unintended”
Clinical Validity
Some definitions of disease are still being defined
Disease spectrum
Reduced penetrance
Pleiotrophy

22. What will this Cost? application type standard fee small business fee†
510(k)‡
$5,018
$2,509
513(g)
$3,387
$1,694
PMA, PDP, PMR, BLA
$250,895
$62,724
panel-track supplement
$188,171
$47,043
180-day supplement
$37,634
$9,409
real-time supplement
$17,563
$4,391
BLA efficacy supplement
PMA annual report
$8,781
$2,195
30-day notice
$4,014
$2,007

23. What will this Cost per “product”?
2010 Stanford study of Device Manufacturers:
24M on average
average cost to take a 510(k) product from concept to market is $31 million, and that roughly 77% of that amount is spent on tasks related to FDA regulation
75M for High Risk PMA
High-risk PMA costs averaged $94 million, the report states, with $75 million of that spent on "stages linked to the FDA."
FDA Impact on U.S. Medical Technology Innovation:
A Survey of Over 200 Medical Technology Companies • November 2010

24. Genetics Lab Cost Estimation Dr
Genetics Lab Cost Estimation Dr. Tanner Hagelstrom, UNMC Presentation at ACMG Meeting March 2015
Assumptions:
Chromosome Analysis falls under Traditional LDT
NGS would require a PMA
FISH + Microarray tests would require a 510(k)
Fixed cost = Total of 3M
PMA = 1.4M
510(k) = 1.6M

25. Genetics Lab Estimation
Variable costs = ~400k per year
Includes 0.5 FTE dedicated to
FDA documentation and management
Anticipated increase in cost of testing:
FISH 185%
Microarray 15%
NGS 25%

26. Again Begs the Question
Is this equation really valid?
Cost FDA Regulation + Delay of Test Release =
Better Health Care

27. Against FDA Regulation
Which Side Are You On?
For FDA Regulation
AdvaMedDx
Against FDA Regulation
ACLA
AMP
CAP
ASCP
ACMG

28. Timeline Final Guidance (no date yet) What comes next:
Have 6 months to complete FDA Notification ( no registration fees)
6 months post Final Guidance MDR regarding LDTs is required
24 months post Final Guidance FDA will release a draft guidance describing what tests they consider to be in the 3 Classes
FDA will address Class III at year 1-5
FDA will address Class II years 4-9

29. How can Soft help? Clinical Validity
Auto-send clinical follow-up and reminder notifications to physicians
Link tests in a group to evaluate results and clinical information
Provide reports of grouped individual results without patient identifiers (in progress)
Query of patients based on test results and indications

30. In Memory of Dr. Warren Sanger

31. Questions