Transcript Document

Oversight of
Laboratory Developed
Tests (LDTs)
Andrew C. Fish, Executive Director
NCCS Cancer Policy Advocate Training
November 13, 2014
Presentation Overview
 Who
is AdvaMedDx?
 What are diagnostics and how are
they currently regulated?
 What are the concerns with LDTs?
 How does FDA plan to oversee
LDTs?
 Questions/Discussion
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What are Diagnostics?
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Diagnostics are tests performed on samples taken from the body,
such as blood, tissue, and urine.
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Clinical Chemistry
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Hematology & Cytology
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Examples : Urinalysis; blood glucose monitor. Measuring
essential chemicals to monitor basic bodily functions and
uncover abnormalities .
Examples : Pap tests; blood cell counts. Assessment of
blood functions; identification of cellular pathologies.
Immunochemistry and Microbiology

Examples : tumor marker tests, HIV antibody tests,
streptococcal throat tests, and urinary tract tests. Detection
and identification of disease -causing agents, like bacteria
and viruses, as well as the proteins, hormones , and anti bodies related to the functions of the body’s immune system.
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What are Diagnostics? cont’d
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Molecular Diagnostics
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Molecular diagnostic tests detect target proteins and
specific genetic sequences (“biomarkers”) to help identify
disease presence, type, progression, and recurrence risk.
 Examples: multivariate -index test to determine risk of
breast cancer recurrence; BRAF mutation test to
determine late stage melanoma patient candidates for
targeted drug therapy.
 These advanced diagnostic tests help clinicians tailor
care to subpopulations and individuals —enabling targeted
“personalized medicine.” An important component of
personalized medicine is the emerging field of companion
diagnostics, in which a molecular diagnostic test is used
to identify whether a specific drug (companion with the
test) is right for an individual patient.
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Cancer Diagnostics
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Screening
Diagnosis (taxonomy of cancer evolving
from site-specific to genetic)
Prognosis/Recurrence Risk
Treatment Selection
Monitoring/Follow up
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Evaluating Diagnostics
 Food,
Drug, & Cosmetic Act: “safe
and effective” as determined by FDA
 Means:
valid – meets claim of what
it measures and how accurately
 Clinically valid – the thing measured is
relevant to the disease (and, in many
cases, to a care decision)
 Analytically
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What is Risk?

Risk = possibility of harm to patient
that could result if test results are
incorrect
 Higher risk:
 When
a false result could lead to incorrect
and harmful clinical management, an
unnecessary invasive procedure, or
failure to follow up on a serious condition

The purpose of FDA review is to assure
availability of safe and effective tests –
for the protection of patients.
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What are Laboratory Developed
Tests?
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Diagnostic tests are
 (1) produced by manufacturers for distribution to
laboratories or other users, or
 (2) produced in and offered by laboratories for
use in their own facilities – these are laboratory
developed tests (LDTs).
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In addition to LDTs used in professional settings,
some labs are marketing their own tests directly to
consumers – including genetic tests claiming to
identify disease risk.
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So What is the Issue?
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Although both statute and regulation cover LDTs, FDA
does not currently enforce its regulations for LDTs.
FDA does enforce regulate diagnostics that manufacturers
sell to laboratories and other users – requiring pre-market
assurance of safety and effectiveness.
Since 1976, FDA has generally exercised enforcement
discretion for LDTs.
Why? Because, at that time, LDTs generally were well understood and relatively simple low risk-tests, or used
for rare conditions for which adequate validation would
not be feasible.
Now, LDTs encompass even the most advanced molecular
diagnostics, such as technically complex genetic tests
that guide cancer treatment.
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Why the Concern with LDTs?
FDA:
 “Diagnostic tests are playing an increasingly important
role in clinical decision making and disease management,
particularly in the context of personalized medicine .”
 “LDTs are often used to assess high -risk but relatively
common diseases and conditions and to inform critical
treatment decisions.”
 “Even when FDA-approved tests are available for a
disease or condition, laboratories often continue to use
LDTs that have not been reviewed by the agency.”
 “LDTs that have not been properly validated for their
intended use put patients at risk. Risks include risk of
missed diagnosis, wrong diagnosis, and failure to receive
appropriate treatment .”
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So Who Oversees Lab
Developed Tests Now?
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The Centers for Medicare and Medicaid Services
(CMS) has oversight authority of clinical
laboratories under the Clinical Laboratory
Improvement Amendments of 1988 (CLIA).
 CLIA establishes laboratory quality standards and
ensures that labs are following good lab practices,
including testing procedures and the employment of
credentialed lab personnel.
But
 CLIA is not a substitute for FDA oversight.
 Only FDA has the resources and expertise to
review LDTs for safety and effectiveness.
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What CLIA Does Not Do
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C M S i t s e l f h a s s a i d C L I A r e g u l a t i o n s a r e n o t a s u b s t i t u te f o r F D A o ve r s i g h t .
M a n y c r i t i c a l f e a t u r e s o f F D A o ve r s i g h t a r e m i s s i n g f r o m C L I A . F u r t h e r m o r e ,
C M S d o e s n o t h a ve t h e e xp e r t i s e o r r e s o u r c e s t o o ve r s e e L D Ts i n t h e s a m e
manner as FDA.
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U n l i k e F D A o ve r s i g h t o f d i a g n o s ti c s , C L I A :
 D o e s n o t r e g u l a t e t h e s a f e t y a n d e ff e ct i ve n e s s o f d i a g n o s t i c t e s t s ;
 D o e s n o t r e q u i r e p r e - m a r k e t r e vi e w o f t e s t s ;
 D o e s n o t r e q u i r e d e m o n s t r a ti o n o f c l i n i c a l va l i d i t y ( wh e t h e r t h e t e s t i s
meaningful for clinical decision making);
 D o e s n o t r e q u i r e s ys t e ma t i c a d ve r s e e ve n t r e p o r t i n g ;
 D o e s n o t h a ve a p r o c e s s f o r c o r r e c t i o n s o r r e c a l l s .
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A t e s t i s a t e s t — a n d p r e s e n ts t h e s a m e r i s k f o r p a t i e n t s r e g a r d l e s s o f
wh e t h e r i t i s d e ve l o p e d b y a m a n u f a c t u r e r o r a l a b o r a t o r y. P o t e n t i a l h a r m s
t o p a t i e n t s wh o s e t e s t s r e t u r n i n c o r r e c t r e s u l t s i n c l u d e u n n e c e s s a r y
t r e a t me n t s , wi t h t h e i r a c c o mp a n yi n g c o s t s a n d s i d e e ff e c t s, a n d t r e a t me n t
d e l a y o r f a i l u r e t o o b t a i n a p p r o p r i a t e t r e a t me n t , a l l o f wh i c h l e a d t o wo r s e
o u t c o me s f o r t h o s e p a t i e n t s .
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Calls for Reform Are Not New
April 2008: HHS Secretary’s Advisory
Committee on Genetics, Health, and
Society (SACGHS) issues report: US
System of Oversight of Genetic Testing: A
Response to the Charge of the Secretary
of Health and Human Services
 Calls upon FDA to “address all laboratory
tests, regardless of how they are produced
(i.e., as a commercial test kit or laboratory developed test)”.
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Stakeholders Endorse FDA Oversight
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Numerous Cancer Advocacy Groups, incl.
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American Cancer Society
American Association for Cancer Research
Ovarian Cancer National Alliance
Cancer Leadership Council
National Coalition for Cancer Survivorship
American Society of Clinical Oncology
American Heart Association
College of American Pathologists
National Health Council
College of American Pathologists
Society for Women’s Health Research
AIDS Institute
Alliance for Aging Research
Men’s Health Network
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FDA Proposed LDTs Framework
October – Draft Guidance: “Framework for
Regulatory Oversight of Laboratory Developed
Tests (LDTs).”
 Defines LDT as a test “intended for clinical use
and designed, manufactured and used within a
single laboratory”
 A risk-based approach – start with high risk tests
and phase in enforcement over time (9 years).
 LDTs divided into current three risk categories –
Class I (low), Class II (moderate), and Class III
(high)
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Exceptions For Low Risk and
Special Needs
Continued Enforcement Discretion
LDTs for solely forensic
LDTs used in organ, stem cell, and
tissue transplantation
Enforcement discretion
re. Premarket Review &
Quality Systems
Requirements*
Low risk LDTs
(Class I)
LDTs for rare diseases
Traditional LDTs
LDTs for unmet needs
*Notification/registration and listing and adverse events reporting required
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LDTs for Rare Diseases
LDTs for
rare
diseases
•must meet definition
of a Humanitarian
Use Device (fewer
than 4,000 patients
per year tested with
the LDT)
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Traditional LDTs
“Traditional
LDTs”
factors
include:
• Both manufactured and used by a
health care facility laboratory (such
as a hospital or clinic) for a patient
being diagnosed and/or treated at
that same health care facility or
within the facility’s healthcare
system
• Comprised of only legally marketed
components and instruments; AND
• Interpreted by qualified lab
professionals, without the use of
automated instrumentation or
software interpretation
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LDTs for Unmet Needs
LDTs for
Unmet
Needs
factors
include:
• Both manufactured and used by a
health care facility laboratory (such
as a hospital or clinic) for a patient
being diagnosed and/or treated at
that same health care facility or
within the facility’s healthcare
system; AND
• No FDA cleared or approved IVD
available for that specific intended
use
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Regulatory Requirements for
All LDTs
Notification or
Registration and listing
Adverse event reporting
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Regulatory Requirements for High and
Moderate Risk LDTs (9 Year Phase In)
Notification or Registration and listing
Premarket review
Quality system requirements
Adverse event reporting
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Implementation Timeline for All
LDTs After Final Guidance
At Six months–
Notification
completed
and/or
Registration
and listing and
adverse event
reporting
At 5 years–
FDA completes
phased-in
enforcement of
premarket
review for Class
III &
commences
Class II Phase
in
At 24 months–
Priority list for
remaining high
risk (Class III)
devices with
submission
starting 12
months later
At 12 months–
Premarket
review for
initial high risk
(class III)
devices
At 4 years–
FDA releases
priority list for
moderate risk
(Class II )
devices
At 9 years–
moderate
risk LDTs
phased in
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What Happens Now?
 Stakeholders
will comment on draft
guidance (comments close February
2 nd )
 FDA
will issue final guidance (timing
uncertain)
 Stay
tuned regarding Congressional
interest
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Questions?