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Another Look at Free Markets – Regulating and Evaluating Genetic Tests
Lawrence Silverman
May 30, 2009
•Oversight of Genetic tests – Roles of FDA, CDC, and CMS and
their relationship with CLIA?
•How Are Genetic Tests Assessed? - What is Analytical Validity, Clinical
Validity, Clinical Utility, and Quality Assurance
•What is Evidence-based Medicine and EGAPP
Another Look at Free Markets – Regulating and Evaluating Genetic Tests
•Oversight of Genetic tests – Roles of FDA, CDC, and CMS and
their relationship with CLIA?
Or,
“It’s Just as Good as a Sony”
•How Are Genetic Tests Assessed? - What is Analytical Validity, Clinical
Validity, Clinical Utility, and Quality Assurance
•Or,
Just Because We Can Perform a Genetic Test, Should We?
•What is Evidence-based Medicine and EGAPP
Or,
Bian Hua (Things Change)
Clinical Laboratory Improvement Amendment
•Passed in 1988 (enacted in 1992) and regulates all clinical
laboratory testing aspects.
•Center for Medicare and Medicaid Services (CMS) - responsible
for CLIA oversight, including financial management of CLIA
operations
•FDA has oversight for laboratory tests under CLIA
•CDC serves an advisory role on CLIA , primarily through
CLIAC (Clinical Laboratory Improvement Advisory Committee)
PCR described
Molecular Diagnosis of
Sickle Cell Anemia using Dystrophin gene
PCR
cloned
1985
1987
1986
Linkage analysis for CF,
DMD, Hemophilia A&B
1988
Direct testing
for DMD
Human Genome
CFTR gene Project starts
cloned
1990
1989
1989
Direct testing
for CF
Regulation of Genetics Tests
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Hot button item
IOM – 1994
Task Force on Genetics Tests – 1997
Secretary’s Advisory Committee on Genetic
Tests – 2001 – analytical validity, clinical
validity, and clinical utility.
• Regulatory gaps
What are Key Issues in Assessing Genetic Tests
Analytical Validity – does the test measure the analyte in question
i.e., can the test detect both the presence and absence of mutations.
Clinical Validity – does the test result predict the presence or absence
of disease
Clinical Utility – how does the test result affect morbidity, mortality, or
disability, specifically through treatments based on the test result.
What is a genetic test and how are they used?
Genetic tests refer to the measurement of DNA, RNA,
chromosomes or proteins that reflect changes in genes or
gene products that are associated with specific disorders or
phenotypes. These disorders may be heritable or acquired.
How genetic tests are commonly used:
Newborn screening, diagnostic testing, carrier testing,
prenatal testing, preimplantation testing, predictive and
presymptomatic testing, identity and forensic testing. Predictive
testing includes pharmacogenomics.
Developing Regulatory Requirements for Genetic Testing
Under CLIA
•Recommendations were made to CLIAC on modifying CLIA to include
a genetic testing specialty. Scope included definitions and
requirements for pre-analytic, analytic and post-analytic phases of
testing – 1997-1999
•Notice of Intent (NOI) – Published in Federal Register 5/2000
notifying that a Notice of Proposed Rule Making was being prepared
to revise CLIA in order to make a human genetics testing specialty.
•57 responses comments were received in response to NOI
•CLIAC Workgroup on Genetic Testing makes recommendations
to public response - 2/2001.
•CMS puts issuance of specialty area on regulatory agenda with
release date of November – 4/2006
•CMS decides a genetic testing specialty is unnecessary since existing
CLIA regulations are sufficient (“It’s just as good as a Sony”) – 9/2006
How Are Genetic Tests Different – Let Me Count the Ways
Penetrance
Expressivity
Modifiers
Epigenetics
De Novo versus inherted
Impriniting
Discrimination (perceived)
Association v causality
Privacy v right to know
Presymptomatic
Predictive
Lack of PT Surveys
2006 Survey of Genetic Testing Laboratory
Directors
• Collect data on genetic testing laboratory PT
practices
• Evaluate participation in PT and laboratory
quality
• Assess views of genetic testing laboratory
directors
Hudson K., J. Murphy, D. Kaufman, G. Javitt, S. Katsanis, and J. Scott.
2006. Oversight of US Genetic Testing Laboratories. Nature Biotechnology
24 (9): 1083-1090.
Survey Results
• 95% of molecular and biochemical testing labs reporting
results to patients are CLIA certified
• 35% of laboratories do not do PT for all of the tests they
perform
• 73% of genetic testing laboratory directors in this survey
support CLIA specialty
FDA and the ASR Rule
“Clinical laboratories that develop tests are acting as manufacturers of
medical devices and are subject to FDA jurisdiction”.
ASR – Analyte Specific Reagent used in laboratory developed tests (LDT)
However, FDA has chosen only to regulate the ingredients of LDTs
(ASRs) since “CLIA regulated labs qualified to perform high complexity
testing have demonstrated expertise and ability to use ASRs in test
procedures and analyses.”
“It’s Just as Good as a Sony”
EGAPP
Evaluation of Genomic Applications in Practice and Prevention
In 2004 CDC established EGAPP to evaluate a systematic,
evidence-based process for assessing genetic tests and other
applications of genomic technology in transition from research to
clinical and public health practice. EGAPP utilizes ACCE criteria
(Analytic and Clinical validity, Clinical utility and associated Ethical,
legal, and social implications) developed by Foundation for Blood
Research in 2004.
Published Recommendations:
•Can Tumor Gene Profiling Improve Outcomes in Patients with
Breast Cancer
•Can UGT1A1 Genotyping Reduce Morbidity and Mortality in
Patients with Metastatic Colorectal Cancer Treated with Irinotecan
•Genetic Testing Strategies in Newly Diagnosed Individuals with
Colorectal Cancer Aimed at Reducing Morbidity and Mortality
from Lynch Syndrome in Relatives
What are Limitations of EGAPP (and ACCE)
Clinical Validity is not regulated under CLIA, which only regulates
performance specifications, such as accuracy, precision, reportable
ranges and reference ranges.
Professional organizations or state agencies that have clearance to
inspect and accredit laboratories can exceed CLIA specifications,
thus, make requirements regarding establishment of clinical
validity. However, this is not universal.
Clinical Utility is both nebulous in definition and dependent on
changing technology, clinical knowledge, and therapy.
Thus, Bian Hua, things change.
Fragile X Premutation and Ovarian
Dysfunction
• Fragile X Syndrome - Most common cause
of inherited mental retardation
• Affects 1:2500-1:4000 males
• Affects 1:5000-1:10000 females
• X-linked mental retardation
1) Mental Retardation-IQ<50 in
affected males, IQ 70-90 in affected
females
2) Characteristic Facies
-low set ears, prominent jaw
3) Behavioural abnormalities
-hyperkinetic
-autistic like behaviour
-learning disabilities
4) Macroorchidism
-Fragile Site induced by culturing in folate depleted media
-Cytogenetic analysis positive in about 60% cases only
-High degree of variability between labs and individuals
-False positives due to other fragile sites in the vicinity
Fragile X Syndrome
Molecular Diagnostics
(CGG)n
>200
Full mutation (inactive, hypermethylated)
55–200 Premutation (not hypermethylated)
45-54 “Grey Zone”
5–44 Normal
CpG
FMR-1
Active
NruI
EcoRI
2.8 kb
5.2 kb
Inactive
EcoRI
Fragile X Sizing in Males
Normal
Male
12 CGGs
Premutation
Male
89 CGGs
Fragile X Sizing in Females
Normal
Females
28/37 CGGs
Premutation
Female
28/78 CGGs
Fragile X Premutation
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Defined as CGG between 55-200
Not hypermethylated; gene not shut down
Individuals do not have fragile X syndrome
Males with premutations pass on only
premutations to their daughters
• Likelihood of passing full mutation from
mother to offspring increases with size of
premutation; 100% likelihood by 90 CGGs
Frequency of Fragile X Premutation
• Differs from study to study
• In women-1:100 to 1:250
• In men-1:250 to 1:750
Premature Ovarian Failure (POF)
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Mean age of menopause is about 51
POF defined as menopause before age 40
About 1% of females have POF
Elevated FSH/LH ratios
Both genetic and environmental causes
known
• However, 60% of cases have no obvious
cause
POF in Fragile X Carriers
• Increased rates of POF found only in premutation
carriers
• About 16-20% of premutation carriers have POF
• Full mutation carriers have no higher incidence of
POF
• High FSH levels (> 15 IU/L) often found in
menstruating women prior to POF
• No changes in inhibin B or 17β estradiol levels
POF in Fragile X Carriers
• Screening of all POF patients led to a pick
up rate of about 1.6-8% for FRA-X
premutations
• Repeat number ranged from 80-175.
• No full mutations were identified
POF and Fragile X Premutation
• Pick up rate for premutation in familial POF
is much higher; about 14-18%
• In sporadic POF 2-4%
What About Premutation Male Carriers?
FXTAS- a new neurologic phenotype
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Several studies have now described the presence of a late-onset neurological
problem in males carriers of the premutation (now termed FXTAS)
Cerebellar ataxia and intention tremor
Other features: short term memory loss, cognitive decline, parkinsonism,
autonomous dysfunction, executive functional defects
MRI shows approx. symmetric increases in T2 weighted signal intensity in
middle cerebellar peduncle
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Eosinophilic intranuclear inclusions found in neurons and astrocytes
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Increasing penetrance of the phenotype with age; >80% by age 80
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Females also affected but severity and penetrance are less
Jacquemont, S. et. al. , JAMA-Jan. 2004
Summary of Regulatory Gaps
• Lack of Genetics Specialty under CLIA
• Lack of FDA oversight for LDT (except ASR)
• Uncertainty regarding clinical validity and clinical
utility
• Inadequacy of PT Surveys for most genetic tests
• Insufficient transparency regarding laboratory
performance