[Federal Register Volume 64, Number 230 (Wednesday, December 1, 1999)]
[Notices]
[Pages 67273-67289]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-31226]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Secretary's Advisory Committee on Genetic Testing
AGENCY: Office of the Secretary, DHHS.
ACTION: Notice of meeting and request for public comments on oversight
of genetic testing.
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Pursuant to Public Law 92-463 notice is hereby given of a meeting
of the Secretary's Advisory Committee on Genetic Testing (SACGT), U.S.
Public Health Service. The meeting will be held from 8:45 a.m. to 5
p.m. on January 27, 2000 at the University of Maryland, School of
Nursing, 655 W. Lombard Street, Baltimore, Maryland 21201. The meeting
will be open to the public from 8:45a.m. to adjournment with attendance
limited to space available. The public is encouraged to register for
the meeting through the SACGT website or by contacting the SACGT at
301-496-9838. Further information about the meeting is available at the
following website address: http://www4.od.nih.gov/oba/sacgt.htm. A
draft meeting agenda will be posted to the website prior to the
meeting. Individuals who plan to attend and need special assistance,
such assign language interpretation or other reasonable accommodations,
should inform the contact person listed below in advance of the
meeting. All comments received before the end of the consultation
period will be considered by SACGT and will be available for public
inspection at the SACGT office between the hours of 8:30 a.m. and 5:00
p.m. The SACGT office is located at 6000 Executive Boulevard, Suite
302, Bethesda, Maryland 20892. Questions about this request for public
comments can be directed to Susanne Haga, Ph.D., Program Analyst,
SACGT, by email ([email protected]) or telephone (301-496-9838).
The Secretary's Advisory Committee on Genetic Testing (SACGT) is
seeking diverse public perspectives on the adequacy of current
oversight of genetic testing in the United States. SACGT was chartered
to advise the Department of Health and Human Services on the medical,
scientific, ethical, legal, and social issues raised by the development
and use of genetic tests. This notice provides background information
prepared by SACGT about genetic tests, including their current
limitations, benefits and risks, and the provisions for oversight now
in place. It presents five specific issues for public comment along
with related questions and a sixth set of questions to enable the
public to comment on other issues relevant to genetic testing. SACGT is
also seeking public comments through a website consultation, a targeted
mailing, and a public meeting on January 27, 2000 in Baltimore,
Maryland.
The public is encouraged to submit written comments on the
oversight of genetic testing to SACGT. In order to be considered by
SACGT, public comments need to be received by January 31, 2000.
Comments can be submitted by mail or facsimile. Members of the public
with Internet access can submit comments through email or the SACGT
website consultation. The SACGT mailing address is: SACGT, National
Institutes of Health, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892. SACGT's facsimile number is 301-496-9839. Comments can
be sent via email to: [email protected]. To participate in SACGT's website
consultation, please visit the SACGT website: http://www4.od.nih.gov/
oba/sacgt.htm Questions about this request for public comments can be
directed to Susanne Haga, Ph.D., Program Analyst, SACGT, by email
([email protected]) or telephone (301-496-9838).
A Public Consultation on Oversight of Genetic Testing
Part I: Introduction
Overview
Decades of research in genetics have brought about many important
medical and public health benefits. Gene discoveries have provided a
better understanding of the genetic basis of disease and opened new
avenues for diagnosis, treatment, and prevention of disease. The pace
of the discovery of new genes and the development of new genetic tests
is expected to increase in the future. The Human Genome Project, a
major international collaborative effort established and supported by
public and private groups, including the U.S. Department of Energy
(DOE) and the National Institutes of Health (NIH), is expected to
complete the sequencing of the human genome by the year 2003. The
unprecedented amount of genetic information produced by the Human
Genome Project will enable scientists to make more rapid progress in
understanding the role of genetics in many common complex diseases and
conditions--such as heart disease, cancer, and diabetes--and to
increase knowledge that may lead to the development of individually
tailored medical treatments. These scientific and technological
advances are expected to bring about revolutionary changes in clinical
and public health practice and to have a significant impact on society.
The Secretary's Advisory Committee on Genetic Testing (SACGT) was
established to advise the Department of Health and Human Services
(DHHS) on the medical, scientific, ethical, legal, and social issues
raised by the development and use of genetic tests. The formation of
SACGT was recommended by the NIH-DOE Task Force on Genetic Testing and
the Joint NIH-DOE Committee to Evaluate the Ethical, Legal and Social
Implications Program of the Human Genome Project. At SACGT's first
meeting in June 1999, the Assistant Secretary for Health and Surgeon
General asked the Committee to assess, in consultation with the public,
the adequacy of current oversight of genetic tests.
Statement of the Issue
Advances in knowledge about the structures and functions of human
genes and the development of new laboratory technologies for the
analysis of genetic material are helping to produce many new genetic
tests for a wide range of conditions and purposes. Genetic tests can be
used to diagnose disease, confirm a diagnosis, provide prognostic
information about the course of disease, confirm the existence of a
disease in individuals who do not yet have symptoms, and, with varying
degrees of effectiveness, predict the risk of future disease in healthy
individuals. Currently, several hundred genetic tests are in clinical
use, with many more under development, and their number and variety are
expected to increase rapidly over the next decade. These
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advances stem in large part from research funded and conducted by
agencies within DHHS, especially NIH.
The Task Force on Genetic Testing, which was charged to review
genetic testing in the United States and to make recommendations to
ensure the development of safe and effective genetic tests, began its
work in 1995 and published its final report two years later. In its
final report, the Task Force concluded that although genetic testing is
developing successfully in the United States, some concerns about it
exist. These can be grouped into four main areas:
The way in which tests are introduced into clinical
practice;
The adequacy and appropriate regulation of laboratory
quality assurance;
The understanding of genetics on the part of health care
providers and patients; and
The continued availability and quality of testing for rare
diseases.
The Task Force recommendations were intended primarily to enhance
the way in which tests are developed, reviewed, and used in clinical
practice. The Task Force explored the question of how tests should be
assessed, considered how comprehensive data gathering efforts could
incorporate new data, and made suggestions about the need for external
review of tests. Although the Task Force recommended that revisions to
the current review process may be needed to assess the effectiveness
and usefulness of genetic tests, it did not specify how the review of
laboratory-based genetic tests should be changed.
DHHS requested that SACGT build on the work of the Task Force by
assessing whether current programs for assuring the accuracy and
effectiveness of genetic tests are satisfactory or whether other
measures are needed. This assessment requires consideration of the
potential benefits and risks (including socioeconomic, psychological,
and medical harms) to individuals, families, and society, and, if
necessary, the development of a method to categorize genetic tests
according to these benefits and risks. Considering the benefits and
risks of each genetic test is critical in determining its appropriate
use in clinical and public health practice. If, after public
consultation and analysis, SACGT finds that other oversight measures
for genetic tests are warranted, it has been asked to recommend options
for such oversight.
It is important to note that although this paper focuses on Federal
oversight of genetic tests in laboratory and clinical settings, the
training and education of health care providers and the promotion of
greater public understanding of genetics are also critical issues. More
genetics training and education of health care providers who prescribe
genetic tests and use the results for clinical decision-making is
widely regarded as another way in which to enhance the safe and
effective development and use of genetic tests. It is helpful to keep
training and education of health care providers and promotion of public
understanding in mind while considering the Federal role in oversight.
SACGT intends to address the training and education issue after this
current assignment is completed.
Importance of Public Consultation
The question of whether more oversight of genetic tests is needed
has significant medical, social, ethical, legal, economic, and public
policy implications. Additional oversight may ensure that genetic tests
are appropriately used and accurately interpreted, and it may increase
the confidence of providers and individuals in using or having genetic
tests. Such oversight might increase the willingness of health insurers
to cover the costs of genetic tests if their usefulness can be
established, but might also increase the costs of those tests. On the
other hand, subsequent acceptance and widespread use of a genetic test
may increase the demand for it and thereby lower the costs of a test.
The development of genetic tests and their use in clinical practice may
be slowed by more oversight measures. Finally, further oversight can be
expected to require additional funds.
Because this issue may greatly affect those who undergo genetic
testing, those who provide tests in health care practice, and those who
work or invest in the development of such tests, DHHS has sought to
ensure that public perspectives on oversight for genetic testing are
considered. Such public involvement in this process will enhance
SACGT's analysis of the issues and the advice it provides to DHHS.
SACGT is hoping to reach a broad audience and to receive a wide range
of perspectives from both professionals and the general public,
including diverse communities. SACGT is using five approaches to gather
public perspectives: (1) A notice in the Federal Register; (2) a
targeted mailing to interested organizations and individuals; (3) a
website consultation (http://www4.od.nih.gov/oba/sacgt.htm); (4) a
public consultation meeting on January 27, 2000 in Baltimore, Maryland;
and, (5) a retrospective review and analysis of the literature. The
Committee looks forward to receiving public comments and to being
informed by the public's perspectives on oversight of genetic testing.
Organization of This Paper
Because the issues surrounding genetic testing are complex and
highly technical, this paper first provides basic background
information about genetic tests, including a discussion of their
current limitations, benefits and risks. The provisions for oversight
that currently are in place are outlined. Then, the paper presents the
specific issues that SACGT and the public have been asked to consider,
along with some possible approaches or options for addressing them.
Part II: Background Information About Genes, Genetics Research, and
Genetic Testing
Overview
Much of the information presented in the following sections
regarding genes, genetics research, and genetic testing is adapted from
Understanding Gene Testing, a booklet produced by the National Cancer
Institute and the National Human Genome Research Institute. The booklet
is available at http://www.accessexcellence.org/AE/AEPC/NIH/index.html.
Genes and Gene Mutations
Genes are made of DNA, a long, threadlike molecule coiled inside
cells. Within the cell, the DNA is packaged into 23 pairs of
chromosomes. Each chromosome, in turn, contains thousands of genes.
Genes, which are segments of DNA, are packets of instructions that tell
cells how to behave. They do so by specifying the instructions for
making particular proteins. The gene instructions are written in a
four-letter code, with each letter corresponding to one of the chemical
constituents, or bases, of DNA: A, G, C, T. The number of bases in the
human genome (the complete sequence of the DNA molecule) is estimated
to be 3 billion to 4 billion. The human genome is estimated to contain
100,000 to 140,000 genes.
If the DNA sequence, the order of the four-letter code, becomes
altered in any way, the cell may make the wrong protein, or too much or
too little of the right one--mistakes that often result in disease. In
some cases, such as sickle cell anemia, just a single misplaced base is
sufficient to cause the disease. Genetic mistakes can be inherited
(called an inherited mutation) or they can develop during an
individual's
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lifetime (an acquired mutation). Inherited mutations are found in every
cell of the body, while acquired mutations occur sporadically in
individual cells.
Mutations in genes are responsible for an estimated 3000 to 4000
clearly hereditary diseases and conditions. Some of these--including
Huntington disease, cystic fibrosis, neurofibromatosis, Duchenne
muscular dystrophy--are caused by the mutation of a single gene. Gene
mutations also play a role in cancer, heart disease, diabetes, and many
other complex diseases. Genetic alterations may increase a person's
risk of developing one of these more complex disorders, although it is
the cumulative effects of the interaction of genetic and environmental
factors, such as diet and smoking, that result in the development of
disease.
Genetics Research
The process of discovering and understanding genetic mutations is
an extremely complex one. Reaching a complete understanding of the
relationship between a mutation and a disease or condition can involve
many years of investigation, and the discovery of a mutation usually is
only the first step. Scientists looking for a gene that contributes to
a particular disease or condition typically begin by studying DNA
samples from members of families in which many relatives over several
generations have developed the same illness--colon cancer, for example.
Scientists start looking for detectable traits or distinctive segments
of DNA (called genetic markers) that are consistently inherited by
relatives with the disease or condition but that are not found in
relatives who do not have it. Then, scientists work to narrow down the
target DNA area, identify possible genes, and look for specific
mutations within those genes.
Because the genome is vast, discovering a specific disease gene
has, up to now, been a difficult and time consuming effort. In the case
of Huntington disease, for example, scientists worked for ten years
before they found the gene that causes the disease. The Human Genome
Project combined with new developments in technology, such as tandem
mass spectrometry, microarrays, and gene chips, will speed up the pace
of the discovery of disease genes and mutations.
Once the entire sequence of the human genome has been mapped,
scientists will have the tools they need to better understand the
contribution of each gene to the development and function of the human
body. Even then, however, the role played by a specific gene mutation
in disease will not be completely understood because of complicating
factors such as gene-gene interactions and environmental influences
(for example, smoking and diet). As a result, understanding what gene
mutations mean for a person's future health and well-being will require
more research, including population-based studies that focus on
clarifying the significance of gene-gene and gene-environment
interactions.
Genetic Testing
Genetic testing involves the analysis of chromosomes, genes, and/or
gene products to determine whether a mutation is present that is
causing or will cause a certain disease or condition. It does not
involve treatment for disease, such as gene therapy, although test
results can sometimes suggest treatment options.
Genetic tests are performed for a number of purposes, including
prenatal diagnosis, newborn screening, carrier testing, diagnosis/
prognosis, presymptomatic testing, and predictive testing. Prenatal
diagnosis is used to diagnose a genetic disorder or condition in a
developing fetus. Newborn screening is used to detect certain genetic
diseases in newborns, and it is performed on a public health basis by
the States. The disorders screened for are those that, if detected
early, have significant treatment or prevention benefits. Carrier
screening is performed to determine whether an individual carries a
copy of a mutated gene for a recessive disease (recessive means that
the disease will occur only if both copies of a gene are mutated).
Carriers are not affected with the disease, but they have a 50 percent
risk of passing the mutation on to their children. If the partner of a
carrier is screened and found also to be a carrier, each child they
conceive will have a 25 percent risk of being affected with the
disorder. Diagnostic testing is used to identify or confirm the
diagnosis of a disease or condition in an affected individual.
Diagnostic testing can also be used for prognostic purposes to help
determine the course of a disease. Presymptomatic testing is used to
determine whether individuals who have a family history of a disease,
but no current symptoms, have the gene mutation. Predictive testing
determines the probability that a healthy individual with or without a
family history of a certain disease might develop that disease.
At present, genetic testing is clinically available for more than
300 diseases or conditions in more than 200 laboratories in the United
States, and investigators are exploring the development of tests for an
additional 325 diseases or conditions. (These statistics were provided
by GeneTests, a directory of clinical laboratories providing testing
for genetic disorders, which can be found at the following website:
http://www.genetests.org). A recent survey of genetic testing
laboratories found that over a recent three-year period, the total
number of genetic tests performed increased by at least 30 percent each
year, rising from 97,518 in 1994 to 175,314 in 1996. Most of the tests
are conducted for diagnostic, carrier, and presymptomatic purposes for
rare genetic disorders. Recently, tests have been developed to detect
mutations for about 25 more common, complex conditions--such as breast,
ovarian, and colon cancer--whose effects generally do not appear until
later in life. These tests are currently used for presymptomatic
purposes in individuals with a family history of the disorder. Although
the tests could be used for predictive purposes, they are not
recommended for this purpose because more must be learned about the
significance of the mutation in someone without a family history of the
disease.
A concern has recently been raised about the impact that patenting
human genes may be having on genetic testing. The Patent and Trademark
Office has been issuing patents on gene sequences since 1980.
Approximately 12,000 patents have been issued on plant, animal, and
human genes and patent applications have been made on another 30,000
genes. While patenting genes generally provides incentives for the
development of useful gene-based products, some gene patent holders
have begun to restrict the use of their gene discoveries by charging
high fees for the license rights, establishing exclusive licenses, or
refusing to license the discovery altogether. These restrictions can
have an adverse effect on the accessibility, price, and quality
assurance of genetic tests. A recent survey conducted by the American
College of Medical Genetics, a professional organization representing
clinical and laboratory geneticists, found that 25 percent of its
members had discontinued offering certain genetic tests because of
patent/licensing complexities.
Important Concepts About the Accuracy and Effectiveness of Genetic
Tests
Several standard terms are used in discussing the accuracy and
effectiveness of laboratory tests. These terms--analytical validity,
clinical validity, and clinical utility--apply not
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only to genetic tests but also to other kinds of tests, such as
cholesterol or pap smear tests. An understanding of these terms is
helpful in considering the possibilities for oversight of genetic
tests.
Analytical validity is an indicator of how well a test measures the
property or characteristic it is intended to measure. (In the case of a
genetic test, the property can be DNA, proteins, or metabolites.) An
analytically valid test would be positive when the relevant gene
mutation is present (analytical sensitivity) and negative when the gene
mutation is absent (analytical specificity). Another element of the
test's analytical validity is reliability--meaning that the test
obtains the same result each time. During the process of validating a
new genetic test, how well it performs will be compared to how well the
best existing method or ``gold standard'' performs. Sometimes, if a
gold standard does not exist for a new genetic test, the test's
performance must be based on how well it performs in samples from
individuals known to have the disease.
Clinical validity is a measurement of the accuracy with which a
test identifies or predicts a clinical condition. A clinically valid
test would be positive if the individual being tested has the disease
or predisposition (clinical sensitivity) and negative if the individual
does not have the disease or predisposition (clinical specificity). To
be clinically valid, a test would be positive if the individual being
tested has or will get the disease or condition (positive predictive
value) and negative if the individual being tested does not have or
will not get the disease or condition (negative predictive value).
Determining the clinical validity of a test may be more challenging
when different mutations within the same gene cause the same disease
and different mutations can result in different degrees of disease
severity. In addition, gene mutations may or may not lead to disease
depending on how ``penetrant'' or completely expressed they are.
Clinical utility refers to the degree to which benefits are
provided by positive and negative test results. If a test has utility,
it means that the results--positive or negative--provide information
that is of value to the person who is tested. The availability of an
effective treatment or preventive strategy, for example, would make
such information valuable. However, even if no interventions are
available to treat or prevent the disease or condition, there may be
benefits associated with knowledge of a result. On the other hand,
social, psychological, and economic harms can result from such
knowledge, particularly in the absence of privacy and discrimination
protections. Thus, determining the clinical utility of a test requires
obtaining information about the benefits and risks of both positive and
negative test results.
A final point can be made about the challenge of assessing the
clinical validity and utility of genetic tests used for predictive
purposes and for rare diseases. For genetic tests used for predictive
purposes in diseases or conditions whose effects do not become apparent
for many years, clinical validity and utility will need to be evaluated
over time. For genetic tests for rare diseases, gathering sufficient
data to assess clinical validity and utility may never be possible
because of the low prevalence of the diseases. Consequently, different
approaches to the evaluation of clinical validity and utility for
predictive tests and for rare disease tests may be necessary.
Current Limitations of Genetic Testing
Genetic tests currently have certain limitations that are relevant
to the issue of oversight. One important limitation is that a test may
not detect every mutation a gene may have. A single gene can have many
different mutations, and they can occur anywhere along the gene.
Moreover, not all mutations have the same effects. For example, more
than 800 different mutations of the cystic fibrosis gene have been
identified, some of which cause varying degrees of disease severity and
some of which appear to cause no symptoms at all. This means that a
positive test for a specific cystic fibrosis mutation may not provide a
clear picture of how the disease is likely to affect the individual. A
negative test result cannot completely rule out the disease because the
test will usually focus only on the more common mutations and will not
detect rare ones. Furthermore, because of varying genetic and
environmental factors, even the same mutations may present different
risks to different people and to different populations. The same
mutation in the cystic fibrosis gene in individuals from different
populations may have different clinical effects as a result of
variations in genetic and environmental factors. In addition, the
frequency of common cystic fibrosis mutations varies among population
groups. Determining the clinical validity of a genetic test requires a
thorough analysis of all these factors without which the likelihood of
error may be high.
Another current limitation of genetic tests, especially if used for
predictive purposes, relates to the complexities of how diseases
develop. Diseases and conditions can be caused by the interaction of
many genetic and environmental factors. Thus, predictive tests cannot
provide certain answers for everyone who might be at risk for a disease
such as breast or colon cancer. For example, mutations in the breast
cancer 1 gene (BRCA1) occur in about half of families with histories of
multiple cases of breast and ovarian cancer. If a woman with no family
history of the disease has the BRCA1 mutation, it may not mean that she
will develop breast or ovarian cancer. Likewise, if she does not have
the mutation, she still cannot be sure she will never develop breast
cancer.
Another important consideration related to the limitations of
genetic testing is that effective treatments are not available for many
diseases and conditions now being diagnosed or predicted through
genetic testing, and, in some instances, they may never be available--a
situation sometimes called the ``therapeutic gap.'' While knowledge
that a disease or condition will or could develop may not provide any
direct clinical benefit, it may lead to increased monitoring which
could help manage the disease or condition more effectively. At the
same time, information about risk of future disease can have
significant emotional and psychological effects and, in the absence of
privacy and anti-discrimination protections, can also lead to
discrimination or other forms of misuse of personal genetic
information.
Potential Benefits and Risks of Genetic Tests
Information provided by genetic tests has potential benefits and
risks. Understanding the benefits and risks of a genetic test is
critical in determining its appropriate use in clinical and public
health practice. The benefits and risks of any particular test to
individuals or particular populations may change over time as more
information is gathered.
Potential Benefits. Individuals with a family history of a disease
live with troubling uncertainties about their and their children's
futures. Having a genetic test may relieve some of those uncertainties.
If the test result is positive, it can provide an opportunity for
counseling and for the introduction of risk-reducing interventions such
as regular screening practices and healthier lifestyles. Early
interventions (for example, annual colonoscopies to check for
precancerous polyps, the earliest signs of colon cancer) could prevent
thousands of colon cancer deaths each
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year. If the test result is negative (they do not have the mutation),
in addition to feeling tremendous relief, individuals may also no
longer need frequent checkups and screening tests, some of which may be
uncomfortable and/or expensive.
Genetic tests can sometimes provide important information about the
course a disease may take. For example, certain cystic fibrosis
mutations are predictive of a mild form of the disease. Other gene
mutations may identify cancers that are likely to grow aggressively.
Genetic tests can provide information to improve treatment
strategies. Because genetic factors may affect how individuals respond
to drugs, the knowledge that an individual carries a particular genetic
mutation can help health care providers tailor therapy. For example,
individuals with Alzheimer disease (AD) who have two copies of a
certain gene mutation do not respond to the drug Tacrine. In
individuals with AD who do not have both copies of the mutation,
however, the drug seems to slow progression of the disease.
Potential Risks. Genetic testing poses potential physical, medical,
psychological, and socioeconomic risks to individuals being tested and
to members of their families. For the most part, the physical risks of
genetic testing are minimal because most genetic tests are performed on
blood samples or cells obtained by swabbing the lining of the cheek.
The procedures required to carry out prenatal genetic testing can, in
rare circumstances, cause miscarriage.
The medical risks of genetic testing relate to actions taken in
response to the results of a genetic test. Positive test results can
have an impact on a person's reproductive and other life choices.
Individuals with positive test results may choose not to have children.
They may opt to take extraordinary preventive measures, such as
surgical removal of the breasts to prevent the possible development of
cancer. Individuals with negative test results may forgo screening or
preventive care because they mistakenly believe they are no longer at
risk for developing a given disease. Incorrect test results or
misinterpretation of test results have substantial risks. False
negative test results can mean delays in diagnosis and treatment. False
positive results can lead to follow-up testing and therapeutic
interventions that are unnecessary, inappropriate, and sometimes
irreversible. Genetic test results have potential psychological risks.
The emotional impact of positive test results can be significant and
can cause persistent worry, confusion, anger, depression, and even
despair. Individuals who have relatives with a disorder have a fairly
clear, and perhaps frightening, picture of what their own future may
hold. Negative test results also can have significant emotional
effects. While most people will feel greatly relieved by a negative
result, they may also feel guilty (survivor guilt) for escaping a
disease that others in the family have developed. A negative test
result may provide a false sense of security because the individual may
still bear the same risk of disease as the general population.
Because genetic test results reveal information about the
individual and the individual's family, test results can shift family
dynamics in pronounced ways. For example, if a baby tests positive for
sickle-cell trait during newborn screening, it means that one of the
parents is a carrier. It is also possible for genetic tests to
inadvertently disclose information about a child's paternity.
Genetic test results present potential socioeconomic risks for
individuals. Some people have reported being denied health insurance
and losing jobs or promotions as a result of genetic test results.
People have reported being rejected as adoptive parents because of
their genetic status. Some people seeking adoptions have requested
genetic testing for the child before finalizing the adoption.
Genetic test results can pose risks for groups if they lead to
group stigmatization and discrimination. Concerns about the potential
risks of discrimination and stigmatization are particularly acute among
minority groups who have experienced other forms of discrimination.
Regrettably, the African American experience with sickle cell anemia
screening provides an example of the potential for and consequences of
discrimination and is one of the reasons why the particular risks of
genetic testing for minority groups must be considered. In the 1970s, a
major effort was made in many States, with Federal Government support,
to screen African American children and young adults for sickle cell
disease. Many of the screening programs were based on an inadequate
knowledge of the genetics of sickle cell disease, and in some
instances, the accuracy and validity of the test itself was in
question. Also, many programs were implemented without sufficient
sensitivity to ethnocultural issues and the potential for misuse of
personal test results. Individuals who were actually carriers of the
mutation were incorrectly identified as having sickle cell disease.
Carriers were ostracized, deprived of employment and educational
opportunities, and denied health and life insurance.
It is important to point out that the potential risks described
above relate to genetic testing for conditions that are solely health-
related. In the future, it may be possible to develop tests that could
be used to diagnose conditions that are related to certain
predispositions, such as to obesity, alcohol abuse, or nicotine
addiction, or to predict future behavior. Although the assumption that
single genes, or even many genes, can predict complex human actions is
simplistic, the possibility of such tests raises profound concerns
because their potential psychological and socioeconomic harms are so
significant and the potential misuse of such information is so great.
Case Studies: From Gene Discovery to the Development and Use of Genetic
Tests
After a gene has been shown to cause or play a role in a specific
disease or condition (through analysis of DNA from affected
individuals), the function of this gene in both healthy and disease
states must then be understood. Each step along the research path adds
to and reshapes existing knowledge in this constantly evolving area of
study. In the following sections, seven case studies are provided to
illustrate the different kinds of genetic testing that are performed,
the way in which genetic tests evolve from research to clinical and
public health practice, and some of the difficulties that can arise
when a test moves from research to clinical use due to limitations in
the data on clinical validity and utility. Although each example
primarily describes one use of the test, it is possible that the same
test could be used for other purposes. For example, a diagnostic test
also may be used for predictive purposes. Indeed, the fact that tests
may be used for multiple and overlapping purposes is one of the
significant challenges of any effort to identify distinct categories of
genetic tests.
Prenatal Diagnosis. An example of a genetic test used for prenatal
diagnosis is the test for the recessive disorder called Tay-Sachs
disease. (Genetic tests are also used for Tay-Sachs carrier screening,
but this case study focuses on its use in prenatal diagnosis.) Tay-
Sachs is a neurological disease that results from a buildup of sugar
fats in brain cells and is caused by a defect in a gene that is
responsible for the breakdown of those fats. Infants with Tay Sachs
generally appear healthy at birth, but begin to develop motor weakness
between 3 and 5 months of age. Progressive weakness continues,
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characterized by poor head control and failure to achieve major
developmental milestones, such as crawling or sitting unsupported.
After 8 to 10 months of age, the disease progresses rapidly, and the
child becomes completely unresponsive. Most children with Tay-Sachs
survive to 2 to 4 years of age; most succumb to pneumonia. Currently,
palliative and supportive treatment is the only therapy for Tay-Sachs
disease.
Prenatal diagnosis of Tay-Sachs disease was first achieved in 1970.
The test involves measuring the activity of a particular enzyme in
cells from a developing fetus. The fetal cells are obtained through two
principal methods--chorionic villus sampling (CVS) and amniocentesis.
CVS, which is performed at 9 to 12 weeks of pregnancy, involves
examining a sample of fetal cells taken from the placenta.
Amniocentesis is a procedure, done at 16 to 18 weeks of pregnancy, in
which a sample of the fluid surrounding the fetus (the amniotic fluid)
is withdrawn from the womb and examined. These procedures carry a risk
of miscarriage (1 case in 100 for CVS and 1 case in 200 to 300 for
amniocentesis). When the results of the Tay-Sachs test are positive,
many couples face an agonizing decision about whether to continue the
pregnancy. Most, but not all, elect to terminate the pregnancy.
Although prenatal diagnosis for Tay-Sachs disease initially was used
only for couples to whom affected children had already been born, it is
now also offered to couples who are identified by carrier screening to
be at risk.
Over the last two decades, the analytical validity and clinical
validity of prenatal testing for Tay-Sachs disease have been
established, and the clinical utility of the test is now also fairly
well understood. Tay-Sachs disease testing is limited primarily to
populations in which the disease is known to be prevalent, including
people of Ashkenazi Jewish or French Canadian descent. The incidence of
Tay-Sachs disease in the Ashkenazi Jewish population is approximately 1
in 4,000 births; in the general population the incidence is tenfold
less (1 in 40,000).
Newborn Screening. Phenylketonuria (PKU) results from a defect in a
gene that encodes for a liver enzyme that is important for the
breakdown of an essential protein building block, phenylalanine. The
defect leads to the buildup of phenylalanine levels in the blood,
resulting in brain damage. It was first described in 1934, when an
association was observed between mental retardation and the presence of
chemicals known as phenylketones in the urine of two siblings. In 1953,
it was demonstrated that lowering blood phenylalanine levels by placing
affected persons on a phenylalanine-restricted diet improves outcomes
for individuals with PKU. In 1959, the introduction of a restricted
diet in PKU-affected newborns was shown to prevent brain damage. The
overall incidence of PKU is approximately 1 in 10,000 live births.
In 1963, a simple, inexpensive test to screen for elevated
phenylalanine in the blood of newborns became available. A trial test
was conducted on a group of individuals with mental retardation, and it
identified correctly all persons who were previously diagnosed with
PKU. After publication of the test method, the PKU screening test was
accepted by the medical and scientific communities and became part of
routine neonatal screening programs across the country. In fact, PKU
was the first genetic disease for which newborn screening was
developed. Newborn PKU screening is required by law in nearly all
States.
The gene responsible for the major form of PKU was found in 1986,
and since then more than 100 different mutations in the gene have been
identified. Because DNA analysis of the PKU gene cannot always be
correlated with disease severity, analysis of enzyme function and
measurement of phenylalanine metabolites are more reliable indicators
of clinical severity.
In the nearly 40 years since the PKU screening test was first used,
a significant amount of data has been collected to establish its
analytical and clinical validity and clinical utility. The test's
clinical utility is especially significant because the most serious
consequence of untreated PKU--mental retardation--can be prevented
through a phenylalanine-restricted diet.
Carrier Screening. Cystic fibrosis (CF), which was first described
in the 1930s, primarily affects the lungs and pancreas and often
results in the onset of chronic lung disease. Recurrent infections and
deficiencies of pancreatic enzymes can prevent normal digestive
function. The median survival of individuals with CF has increased from
18 years in 1976 to 30 years in 1995, thanks to aggressive management
of disease complications. CF is most common in people of northern and
central European origin, with an incidence of 1 in 2,000, but it is
much less common in other populations.
The CF gene was identified in 1989. Seventy percent of affected
individuals carry the same mutation in the CF gene, and about 30 other
mutations account for another 20 percent of CF cases. The remaining 10
percent have been found to have one of at least 800 additional
mutations, and new mutations are still being identified. More than 85
percent of individuals with CF are born to parents who have no family
histories of the disorder.
Results from a CF carrier test can only reduce--not eliminate--the
risk that one may be a carrier, because it is not practical to test for
all of the possible rare mutations. Carrier screening is recommended
for those individuals with family histories of CF or for those who have
a relative identified as a CF carrier. An NIH consensus development
conference in 1997 concluded that carrier screening should be offered
to all pregnant women and couples contemplating pregnancy, but this
recommendation is in the early stages of implementation. Further
research is needed to correlate the many different gene mutations with
disease severity, population differences, and penetrance. Information
from these studies may aid in an assessment of the clinical validity
and clinical utility of broader based carrier screening.
Diagnostic/Presymptomatic Testing. Testing for myotonic dystrophy
can be both diagnostic and presymptomatic. First described in 1908,
myotonic dystrophy is an autosomal dominant, multisystem disorder
mainly involving the heart, smooth and skeletal muscle, central nervous
system, and eyes. The incidence of myotonic dystrophy is 1 in 8,000. It
is characterized by a symptom known as myotonia-delayed muscular
relaxation or stiffness and is extremely variable in severity both
within and between families. The disease has been shown to have an
earlier onset and increasingly severe clinical features as it is passed
from one generation to the next.
The gene for myotonic dystrophy was identified in 1985. The
mutation is located at one end of the gene, where a series of duplicate
DNA sequences called repeats is found. In the normal gene, the number
of repeats is fewer than 50. Carriers of the myotonic dystrophy gene
have 50 to 80 repeats; affected adults have between 100 to 500 repeats.
Several studies have found a correlation between a higher number of
repeats and earlier age of onset and disease severity.
Molecular testing for diagnostic and presymptomatic purposes has
been used for myotonic dystrophy since 1990, and DNA testing is now an
acceptable form of diagnosis for this disease. More than 1,000
individuals have been studied through DNA analysis, and thus far, no
mutation other than the increased number of repeat sequences has been
found. Data on the analytical validity and clinical validity of this
test are
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fairly complete, but unfortunately, no specific therapy is available
that will slow or significantly modify the progressive muscular changes
that occur in individuals with myotonic dystrophy. Although the test is
able to provide a definitive diagnosis and is considered useful for
some individuals, the clinical utility of the test is less clear-cut
because of the lack of effective treatment. Scientists are hopeful that
further research on the function of the myotonic dystrophy gene may
explain the underlying causes of the disease and lead to the
development of new therapies.
Diagnostic Testing (with effective treatment). Genetic testing for
hereditary hemochromatosis (HH) is currently conducted for diagnostic
purposes. Studies are underway to determine whether the genetic test
should be used for predictive purposes in the general population. HH
was first described in 1889. It is an autosomal recessive disease that
results in increased accumulation of iron in the body. When the body's
storage capacity for iron is surpassed, the iron is deposited in the
tissues of multiple organs, causing tissue damage. This iron overload
can cause cirrhosis of the liver, diabetes, fatigue, and heart disease,
among other conditions, and persons with HH are more likely to die from
liver failure or primary liver cancer. However, HH is one of the few
genetic diseases for which an effective and relatively simple therapy
exists if the disease is diagnosed before tissue damage has occurred.
The therapy involves removing excess iron by periodic phlebotomy, or
bloodletting.
In 1972, a simple biochemical test was developed to measure iron
levels in the blood. The accuracy of the test was evaluated through
several investigational studies. It is currently the most common
screening strategy for the disease. The incidence of HH is estimated to
be about 3 in 1,000 in people of northern European descent, an estimate
that is based on screening trials that used biochemical measures of
iron overload to identify affected persons. The proportion of people
with positive test results who progress to symptomatic disease or life-
threatening complications is unknown, however, and information on the
incidence of HH in other populations is less complete.
In 1996, more than 100 years after HH was first described, the gene
responsible for HH was identified. Based on research studies of HH
affected individuals, one specific mutation in the gene has been found
to be responsible for 85 percent of HH cases, and a second mutation is
responsible for a much smaller proportion of cases. More than a dozen
different genetic testing methods are now available for the detection
of the two described mutations. Genetic testing for HH has been used to
identify presymptomatic persons with a family history, and it may
eventually replace liver biopsy as the definitive test for HH because
it is safer and noninvasive. Broad-based population screening by DNA
analysis has not been implemented for HH because of the uncertain link
between positive test results and severity of disease, the
environmental and other genetic factors that may be involved in the
disease process, and the possibility that other mutations may exist
that have not yet been identified. Studies are underway to address
these knowledge gaps and to assess the clinical validity of the DNA
based test.
Diagnostic/Predictive Testing (without effective treatment).
Alzheimer disease (AD), which was first described in the early 1900s,
is a progressive disease that causes impairment in multiple brain
functions, including memory, language, orientation, and judgment. The
only definitive diagnosis for AD is the examination of brain tissue
after death. At the present time, a checklist of clinical symptoms is
used to diagnose AD and to rule out other possible disorders. Thus, a
definitive diagnostic test for AD would be an important medical
advance. Three genes have recently been associated with AD, although
inherited cases of AD make up only a small proportion (less than two to
five percent) of AD sufferers. Diagnostic and presymptomatic testing
based on DNA analysis is recommended only for the small number of
families that have a dominant pattern of inheritance of AD in multiple
generations. A fourth gene, known as APOE, is the most recent gene
found to be associated with AD. One variant of the gene, referred to as
APOE4, is thought to be a risk factor for AD. Although the majority of
AD cases occur at random, individuals with one or two copies of this
gene are thought to be at greater risk for developing AD than the
general population.
Not long after the discovery of this association, the test was
commercialized as a tool to predict heightened risk for AD, although
the clinical validity and clinical utility of the test had not yet been
established. Subsequently, APOE4 predictive testing was withdrawn from
the market, and the test is now available only to aid in the
confirmation of a diagnosis of AD in a patient showing signs of
dementia. APOE4 predictive DNA testing for AD is not recommended for
several reasons. First, it is associated at a population level with an
increased risk of AD, but its predictive value for individuals is
limited because many people with one or two copies of APOE4 will never
develop AD, and conversely, many people with AD do not carry the gene
variant. In addition, science's understanding of other risk factors
that may play a role in the development of the disease in people who
carry APOE4 is limited. Finally, the social and psychological burdens
of predictive AD testing are not understood fully, and treatment and
preventive strategies are lacking. More research into the genetic basis
of AD will be necessary before predictive genetic testing of AD in the
general population would be appropriate.
The ongoing commercial availability of this test as a tool in
diagnosing AD complicates oversight issues, because without appropriate
oversight, the APOE4 test could be used for predictive purposes, even
though this use is not recommended. In addition, a positive result from
APOE4 testing in an individual suspected of having AD automatically
provides information to relatives about their probability of developing
the disease, information that could be misused. As this example shows,
the boundary between predictive and diagnostic uses of tests often is
not distinct.
Presymptomatic/Predictive Testing. Breast cancer is an example of a
disease in which genetic testing is used to predict disease in
individuals with a family history of the disease. According to recent
estimates, breast cancer is the second leading cause of cancer death in
women in the United States. One out of every eight American women is at
risk for developing breast cancer during her lifetime. There are a
number of treatment options for breast cancer, including radiation,
lumpectomy or mastectomy, and multiple drug treatments for both first
diagnosis and metastatic disease. However, there is no guaranteed cure,
and, once diagnosed, women never know whether they will be able to
overcome the disease. Women with a strong family history of breast
cancer, which may suggest the presence of a genetic factor, are at
greater risk, although only 5 to 10 percent of breast cancer cases are
believed to be related to genetic predisposition.
Because of the strong family history documented in some women who
develop breast cancer, scientists began an intensive search for the
gene that contributes to the development of this disease. DNA from
women with familial breast cancer was analyzed, and in 1990, a region
on chromosome 17 was found to be linked to increased risk for
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the development of breast and ovarian cancer. In 1994, the BRCA1 gene
was identified as a cancer-susceptibility gene. A second gene, BRCA2,
was later discovered. Mutations in these two genes account for a
significant portion of inherited cases of breast and ovarian cancer.
Development of commercial tests for these genes quickly followed.
However, difficulties in assessing the analytical and clinical validity
of BRCA1/2 test results have been demonstrated in some studies.
Hundreds of mutations have been detected in the two BRCA genes, and
different mutations in these genes may have different risks for breast
cancer and ovarian cancer, or possibly different affects of tumor
progression or severity. This suggests that further research is
necessary to clarify the relationship between gene mutations in BRCA1/2
and the risk of developing breast and/or ovarian cancer. Studies have
shown that the same mutations in different families have resulted in
different disease outcomes, and environmental and other modifying
factors also may determine how a particular mutation behaves, further
contributing to the difficulty in interpreting BRCA 1/2 test results.
The complexities associated with genetic testing of BRCA1/2 raise
further concerns, because some of the options a woman may choose if she
tests positive, such as the surgical removal of breasts or ovaries, are
irreversible. Further research on different populations and on women
with no family history of breast cancer are necessary to establish
analytical and clinical validity for BRCA1/2 testing in the general
population. Such research should also increase understanding of the
risks and benefits of testing for these groups, which may be different
for women with no family history of the disease.
Part III: Current Oversight of Genetic Tests
In considering whether additional oversight measures for genetic
tests are needed, it is important to understand the provisions for
oversight that already are in place. Currently, genetic and non-genetic
tests receive the same level of oversight from governmental agencies.
Genetic tests are regulated at the Federal level through three
mechanisms: (1) The Clinical Laboratory Improvement Amendments (CLIA);
(2) the Federal Food, Drug, and Cosmetic Act; and (3) during
investigational phases, regulations for the Protection of Human
Subjects (45 CFR 46, 21 CFR 50, and 21 CFR 56). In addition to the
Federal role, oversight of genetic tests is provided by States and
private sector organizations.
This section summarizes the roles of five DHHS organizations in
providing oversight of genetic tests: the Centers for Disease Control
and Prevention (CDC), Food and Drug Administration (FDA), Health Care
Financing Administration (HCFA), Office for Protection from Research
Risks (OPRR), and National Institutes of Health (NIH). Although it does
not have a regulatory function, the NIH supports research activities
that generate knowledge about genetics and genetic testing. The roles
of the States and the private sector in oversight also are described.
The Roles of CDC and HCFA
All laboratory tests performed for the purpose of providing
information for the health of an individual must be conducted in
laboratories certified under CLIA. Tests are regulated according to
their level of complexity: waived, moderate, and high complexity. The
regulatory requirements applied to these laboratories increase in
stringency with the complexity of the tests performed. Under CLIA,
HCFA's Division of Laboratories and Acute Care in partnership with
CDC's Division of Laboratory Systems develops standards for laboratory
certification. In addition, the CDC conducts studies and convenes
conferences to help determine when changes in regulatory requirements
are needed. The advice of the Clinical Laboratory Improvement Advisory
Committee (CLIAC) may also be sought regarding these matters.
The CLIA program provides oversight of laboratories through on-site
inspections conducted every two years by HCFA using its own scientific
surveyors or employing surveyors of deemed organizations or State-
operated CLIA programs that have been approved for this purpose. The
oversight provided includes a comprehensive evaluation of the
laboratory's operating environment, personnel, proficiency testing,
quality control, and quality assurance. The laboratory director, who
must be certified, plays a critical role in assuring the safe and
appropriate use of laboratory tests. Laboratory directors are required
to take specific actions to establish a comprehensive quality assurance
program, which ensures that the continued performance of all steps in
the testing process is accurate. Although laboratories under CLIA are
responsible for all aspects of the testing process (from specimen
collection through specimen analysis and reporting of the results), to
date, CLIA oversight has emphasized intra-laboratory processes as
opposed to the clinical uses of test results. CLIA has not specifically
addressed other aspects of oversight that are critical to the
appropriate use of a genetic test, including the clinical validity and
clinical utility of a given test. Also unaddressed to date are other
important issues such as informed consent and genetic counseling. (See
Part IV for a discussion of steps being taken by CDC and HCFA to
strengthen CLIA regulations for genetic testing.)
The Role of FDA
All laboratory tests and their components are subject to FDA
oversight under the Federal Food, Drug, and Cosmetic Act. Under this
law, laboratory tests are considered to be diagnostic devices, and
tests that are packaged and sold as kits to multiple laboratories
require premarket approval or clearance by the FDA. This premarket
review involves an analysis of the device's accuracy as well as its
analytical sensitivity and specificity. Premarket review is performed
based on data submitted by sponsors to scientific reviewers in the
Division of Clinical Laboratory Devices in the FDA's Office of Device
Evaluation. In addition, for devices in which the link between clinical
performance and analytical performance has not been well established,
the FDA requires that additional analyses be conducted to determine the
test's clinical characteristics, or its clinical sensitivity and
specificity. In some cases, the FDA requires that the predictive value
of the test be analyzed for positive and negative results.
The majority of new genetic tests are being developed by
laboratories for their own use. These are referred to as in-house tests
or ``home brews.'' The FDA has stated that it has authority, by law, to
regulate home brew laboratory tests, but the agency has elected, as a
matter of enforcement discretion, not to exercise that authority.
However, the FDA has taken steps to establish a measure of regulation
of home brew tests by instituting controls over the active ingredients
(analyte-specific reagents) used by laboratories to perform genetic
tests. This regulation subjects reagent manufacturers to certain
general controls, such as good manufacturing practices. However, with
few exceptions, the current regulatory process does not require a
premarket review of the reagents. (The exceptions involve certain
reagents that are used to ensure the safety of the blood supply and to
test for high-risk public health problems such as HIV and
tuberculosis.) The regulation restricts the sale of reagents to
laboratories capable of performing high-complexity tests and requires
that certain information
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accompany both the reagents and the test results. The labels for the
reagents must, among other things, state that ``analytical and
performance characteristics are not established.'' Also, the test
results must identify the laboratory that developed the test and its
performance characteristics and must include a statement that the test
``has not been cleared or approved by the U.S. FDA.'' In addition, the
regulation prohibits direct marketing of home brew tests to consumers.
The Role of Human Subjects Regulations
Additional oversight is provided during the research phase of
genetic testing if the research involves human subjects or identifiable
samples of their DNA. Regulations governing the protection of human
research subjects are administered by the OPRR and FDA. OPRR oversees
the protection of human research subjects in DHHS-funded research. The
FDA oversees the protection of human research subjects in trials of
investigational (unapproved) devices, drugs, or biologics being
developed for eventual commercial use. Fundamental requirements of
these regulations are that experimental protocols involving human
subjects must be reviewed by an organization's Institutional Review
Board (IRB) to assure the safety of the subjects and that risks do not
outweigh potential benefits. The regulations apply if the trial is
funded in whole or in part by a DHHS agency or if the trial is
conducted with the intent to develop a test for commercial use.
However, FDA regulations do not apply to laboratories developing home-
brew genetic tests, because at present these tests are not subject to
the FDA's enforcement authority. OPRR regulations would apply if the
laboratory was DHHS-funded or was carrying out the research at an
institution that receives DHHS funding. In a 1995 survey of
biotechnology companies, the Task Force on Genetic Testing found that
46 percent of respondents did not routinely submit protocols to an IRB
for any aspect of genetic test development.
The Role of NIH
The mission of NIH is to support and conduct medical research to
improve health. This research encompasses basic, clinical, behavioral,
population-based, and health services research. In addition to funding
a substantial amount of genetics research, including the Human Genome
Project, and assuring that the research is conducted in accordance with
human subjects regulations and other pertinent guidelines, NIH supports
a number of other programs that have an important role in disseminating
knowledge and technology to the public and private sectors. These
activities help promote the appropriate integration and application of
scientific knowledge into clinical and public health practice. The
following are examples of research, dissemination, and integration
activities supported wholly or in part by NIH that might specifically
contribute to a better understanding of the validity and utility of
genetic tests.
The Ethical, Legal, Social Issues (ELSI) Program, a major
program established as an integral part of the Human Genome Project,
supports research on the ethical, legal, and social implications of
human genetics research.
A five-year epidemiologic study of iron overload and
hereditary hemochromatosis is beginning to gather data on the
prevalence, genetic and environmental determinants, and potential
clinical, personal, and societal impact of the disorder. The knowledge
gained from this study will be used to determine the feasibility,
benefits, and risks of a broad-based screening program.
The Cancer Genetics Network, a consortium of academic
cancer centers around the country, serves as a national resource to
support multi-center investigations into the genetic basis of cancer
susceptibility, to integrate new research data into medical practice,
and to identify psychological, ethical, legal, and public health issues
related to cancer genetics.
GeneTests, a directory of clinical laboratories providing
testing for genetic disorders, disseminates information about diseases
and diagnostic and treatment options to health care providers and the
public.
The National Coalition for Health Professional Education
in Genetics promotes genetics education and information dissemination
to health professionals.
NIH also produces consensus statements and technology assessment
statements on issues important to health care providers, patients, and
the general public. Topics related to genetic testing have included
newborn screening for sickle cell disease, genetic testing for cystic
fibrosis, and screening for and management of PKU.
The Role of the States
State health agencies, particularly state public health
laboratories, have an oversight role in genetic testing, including the
licensure of personnel and facilities that perform genetic tests. State
public health laboratories and State-operated CLIA programs, which have
been deemed equivalent to the Federal CLIA program, are responsible for
quality assurance activities. A few States, such as New York, have
promulgated regulations that go beyond the requirements of CLIA. States
also administer newborn screening programs and provide other genetic
services through maternal and child health programs.
The Role of the Private Sector
The private sector provides oversight in partnership with HCFA and
the CDC by serving as agents for the Government in accreditation
activities. The private sector also develops laboratory and clinical
guidelines and standards. A number of organizations are involved in
helping to assure the quality of laboratory practices and in developing
clinical practice guidelines to ensure the appropriate use of genetic
tests. These organizations include the College of American Pathology
(CAP), which develops standards for its membership and establishes and
operates proficiency testing programs; the NCCLS (formerly called the
National Committee on Clinical Laboratory Standards), which develops
consensus recommendations for the standardization of test
methodologies; and, the American College of Medical Genetics (ACMG),
which develops guidelines for the use of particular tests and test
methodologies and works with CAP to provide proficiency tests for
certain genetic tests. Other organizations, such as the American
Academy of Pediatrics, American College of Obstetrics and Gynecology,
American Society of Human Genetics, and National Society of Genetic
Counselors, are also involved in the development of guidelines and
recommendations regarding the appropriate use of genetic tests.
The Roles Combined
It is likely that no single agency or organization will be able to
address all the issues raised by genetic tests. Instead, the combined
expertise of all entities may be needed.
Part IV: Recommendations of the NIH-DOE Task Force on Genetic
Testing
The Task Force on Genetic Testing made a number of recommendations
related to the oversight of genetic tests. The Task Force identified
the type of data needed in order to assess the validity and utility of
genetic tests, methods of data collection, preliminary criteria for
tests that require stringent scrutiny, the need for external review of
genetic tests, steps for enhancing
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laboratory quality assurance, and special concerns related to rare
diseases. These recommendations are summarized below, and the full
report of the Task Force is available at www.nhgri.nih.gov/ELSI/
TFGT__final/. The actions taken by the Federal agencies in response to
the Task Force recommendations are also outlined.
Data needed for assessing tests. The Task Force recommended that
data regarding analytical and clinical validity and clinical utility
should be gathered to determine when a test is ready for clinical
application and that validation should occur for each intended use of a
test.
Collection of data. The Task Force recommended that NIH and the CDC
support consortia and other collaborative efforts to facilitate data
collection on test safety and effectiveness. It recommended that the
CDC play a coordinating role in data gathering and serve as a
repository for data submitted by genetic test developers.
Tests requiring stringent scrutiny. The Task Force recommended that
certain kinds of genetic tests might require a higher level of
scrutiny, and it suggested some criteria for determining which kinds of
tests these might be. The criteria included whether
The tests are used for predicting future disease in
healthy or apparently healthy people;
The tests cannot be independently confirmed;
The tests have low sensitivity and low positive predictive
value;
The tests are for conditions for which an intervention is
not available or has not been proven effective in those with positive
test results;
The tests are for disorders of high prevalence;
The tests are for screening; and
The tests are likely to be used selectively in
ethnocultural groups with higher incidence or prevalence of a disorder.
Review of genetic tests. The Task Force recommended that test
developers submit their clinical validity and utility data to
independent internal and external reviewers and to interested
professional organizations. It said that the reviews should ensure that
the data are interpreted correctly, that test limitations are
described, and that the populations for which the test may or may not
be appropriate are defined.
Enhancing laboratory quality assurance. The Task Force recommended
that CLIA regulations be augmented to strengthen clinical laboratory
practices for genetic tests by requiring specific provisions for
quality control, personnel qualifications and responsibilities, patient
test management, proficiency testing, quality assurance,
confidentiality, and informed consent. The Task Force recommended that
clinical laboratories should not offer a genetic test unless its
clinical validity has been established or data on its clinical validity
are being collected either under an IRB-approved protocol or a
conditional premarket approval agreement from the FDA. It also
recommended that clinical laboratories pilot a test in order to verify
that all steps in the testing process are operating appropriately.
Ensuring continuity and quality of tests for rare diseases. The
Task Force pointed out that although the vast majority of single-gene
diseases are rare, a total of 10 to 20 million Americans are afflicted
with rare diseases. The Task Force recommended that laboratories
providing genetic testing services for rare diseases should be CLIA-
certified, subject to the same internal and external reviews as other
clinical laboratories, and required to validate tests used in clinical
practice. It further suggested that, because of difficulties in
obtaining sufficient data on test validity, consideration should be
given to developing less stringent regulations--without sacrificing
quality--for genetic testing of rare diseases. The Task Force
highlighted the important role of the NIH Office of Rare Diseases in
disseminating information about the availability of safe and effective
tests for rare diseases.
Progress Since Publication of Task Force Report
Since receiving the final report of the Task Force on Genetic
Testing, DHHS agencies have acted on several of the Task Force
recommendations that relate to the oversight of genetic tests. The FDA
promulgated the regulation described in Part III for components of
tests, thereby introducing a degree of FDA oversight of commercial,
laboratory-based testing services. The FDA also has established an
advisory panel on genetics to provide expertise needed for the review
of genetic test kits.
HCFA and CDC have taken steps to develop recommendations for more
specific requirements for the performance of genetic tests under CLIA.
After careful review of existing requirements, CLIAC recommended
changes to ensure that CLIA specifically addresses genetic testing. The
CLIAC recommendations include provisions for the pre-and post-
analytical phases of the testing process. The pre-analytical provisions
include attention to the need for informed consent prior to collecting
the sample. The informed consent process helps individuals understand
the risks and benefits of a specific test so that they can make
informed decisions regarding genetic testing. Clinical information,
including ethnic background, when appropriate, would need to be
submitted to the laboratory performing the test in order to enhance the
accuracy of the interpretation of results. This is because although a
given test may be likely to predict disease in some populations, it may
produce unacceptable false positive results in another ethnic group. To
ensure accuracy, samples would have to be transported to the testing
laboratory in a manner that would preserve the integrity of the DNA,
RNA, protein, or metabolite to be studied. For the post-analytical
phase, CLIAC recommended additional requirements for assuring the
confidentiality of test results as they are returned to the provider.
The security of test information is essential to protecting the privacy
of test results, especially when a number of locations require access
to the information or results are communicated using computers. To
avoid over- or under-interpreting the meaning of test results, CLIAC
recommended that they be described clearly, including detailed
information about the methods used and the specific factors tested.
Counseling must be readily available to help individuals understand the
meaning of the specific test that was performed and the significance of
the findings to other family members. These and other post-analytical
factors require thoughtful design and implementation in order to ensure
that the performance of the genetic test maximizes benefits to
individuals and families and minimizes socioeconomic risks. The CLIAC
recommendations will be published in the Federal Register for public
comment. Comments will be reviewed and carefully considered before
final changes are made to CLIA.
CDC has established the Human Genome Epidemiology Network to
advance the collection, analysis, dissemination, and use of peer-
reviewed epidemiologic information on human genes. The Network promotes
the use of this knowledge base for making decisions involving the use
of genetic tests and services for disease prevention and health
promotion by health care providers, researchers, members of industry
and government, and the public.
CDC is leading an interagency effort to explore how voluntary,
public-private partnerships might help encourage and facilitate the
gathering, review and
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dissemination of data on the clinical validity of genetic tests. Such
data collection through a consortium approach is important for several
reasons. In addition to the increasing number of predictive tests for
common chronic diseases and potential for commercialization and
premature use of genetic tests, there is a need for making consistent
information available to providers, consumers, and policymakers. Also,
the evaluation of tests may require longitudinal clinical and
epidemiologic data, data that are generated from both public and
private sources. The goals of the public/private partnership include
identifying data elements needed for the evaluation of genetic tests,
exploring a framework for data collection and dissemination, and
facilitating the review of data for a smoother transition from gene
discovery to clinical and public health. Two pilot data collection
efforts for cystic fibrosis and hereditary hemochromatosis are in the
preliminary stages.
The CDC, NIH, the Health Resources and Services Administration
(HRSA), and the Agency for Health Care Policy and Research (AHCPR) are
beginning to collaborate more closely to promote and support the
development of genetic knowledge and technology and to ensure that this
knowledge and technology is used appropriately to improve the health
and well being of the Nation. The goal of this collaboration is to
enhance agency programs involving technical assistance, professional
and public education, data collection and surveillance, applied genetic
research and assessment, policy development, and quality assurance.
Part V: Critical Issues To Be Addressed
SACGT has been asked to assess, in consultation with the public,
whether current programs for assuring the accuracy and effectiveness of
genetic tests are satisfactory or whether other oversight measures are
needed for some or possibly all genetic tests. This assessment requires
consideration of the potential benefits and risks (including
socioeconomic, psychological, and medical harms) to individuals,
families, and society, and, if necessary, the development of a method
to categorize genetic tests according to these benefits and risks.
Considering the benefits and risks of each genetic test is critical in
determining its appropriate use in clinical and public health practice.
If, after public consultation and analysis, SACGT finds that other
oversight measures are warranted, it has been asked to recommend
options for such oversight. The advantages and disadvantages of each
option must be considered carefully before a final determination is
made.
SACGT has been asked to address these five specific issues.
Issue 1: What criteria should be used to assess the benefits and
risks of genetic tests?
Issue 2: How can the criteria for assessing the benefits and
risks of genetic tests be used to differentiate categories of tests?
What are the categories and what kind of mechanism could be used to
assign tests to the different categories?
Issue 3: What process should be used to collect, evaluate, and
disseminate data on single tests or groups of tests in each
category?
Issue 4: What are the options for oversight of genetic tests and
the advantages and disadvantages of each option?
Issue 5: What is an appropriate level of oversight for each
category of genetic test?
These five issues are discussed in more detail below. This
discussion is provided in order to foster public discussion and
deliberation. Following the discussion of each major issue, SACGT
presents a number of related questions. SACGT encourages public comment
on all or any one of the major issues and approaches and on the related
questions. SACGT presents a sixth set of other related questions
relevant to genetic testing and encourages public input on these as
well.
Issue 1: What Criteria Should Be Used To Assess the Benefits and Risks
of Genetic Tests?
Assessing the benefits and risks of genetic tests is a process that
occurs in stages. Before a test is used in clinical or public health
practice, a determination must be made regarding the test's
effectiveness in the laboratory--that is, whether a test is
analytically valid. The degree of complexity of the test is a
particularly important factor in assessing analytical validity. The
second step in assessing the benefits and risks of genetic tests is to
evaluate how well tests perform in the clinical environment, which is
the principal focus of discussion for this issue.
In considering this issue, SACGT identified three primary criteria
that could be used to assess the benefits and risks of a genetic test.
One criterion is clinical validity, which refers to the accuracy of the
test in diagnosing or predicting risk for a health condition. Clinical
validity is measured by the sensitivity, specificity, and predictive
value of the test. The second criterion is clinical utility, which
involves identifying the outcomes associated with positive and negative
test results. Because clinical validity and clinical utility of a
genetic test may vary depending upon the health condition and the
population to be tested, these criteria must be assessed on an
individual basis for each test. The third criterion relates to the
social context within which genetic testing is performed.
Factors To Be Considered in Assessing Clinical Validity
Because clinical validity considers many aspects of genetics that
make genetic testing complex, it is a measure that is essential to the
assessment of the benefits and risks of genetic tests. A test's
clinical validity is influenced by a number of factors beyond the
laboratory, including the purpose of the test, the prevalence of the
disease or condition tested for, and the adequacy of relevant
information.
Purpose of test. Genetic tests have a number of purposes, and some
are used for more than one purpose. The acceptable level of a
predictive value of a genetic test may vary depending on the purpose
for which the test is used (for example, for diagnosing or predicting a
future health risk). In addition, a higher predictive value may be
required of a stand-alone test than of a test that is used to confirm
other laboratory or clinical findings.
Prevalence. Clinical validity, particularly predictive value, is
influenced by the prevalence of the condition in the population.
Assessing clinical validity may be particularly challenging in the case
of tests for rare diseases. This is because gathering statistically
significant data may be difficult, as relatively few people have these
diseases. Thus, prevalence may be a factor in determining how much data
on test performance should be available before a test is offered in
patient care.
Adequacy of information. For many genetic tests, particularly those
used for predicting risk, knowledge of the test's clinical validity may
be incomplete for many years after the test is developed. When
information that may affect clinical validity is incomplete, the
potential harms of the test may increase and must be considered more
carefully.
Factors To Be Considered in Assessing Clinical Utility
Clinical utility is the second criterion that is critical to
assessing the benefits and risks of genetic tests. Clinical utility
takes into account the impact and usefulness of the test results to the
individual, the family, and society. The benefits and risks to be
considered include the social and economic consequences of testing as
well as the implications for health outcomes. Decisions about the use
of a genetic test
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should be based upon a consideration of the risks of any follow-up
tests required to confirm an initial positive test, of the degree of
certainty with which a diagnosis can be made, and of the potential for
adverse socioeconomic effects versus beneficial treatment if a
diagnosis is made. Factors affecting clinical utility include the
potential benefits and risks of test results, the nature of the health
condition and its potential outcomes, the purpose of the test,
uncertainties of genetic test results, the provision of information
concerning other family members, and the quality of evidence for
assessing outcomes.
Potential benefits and risks of genetic test results. There are a
number of potential benefits and risks of genetic testing. The benefits
and risks of true positive and negative test results must be
considered, as must the risks of false positive and negative results
(see list of benefits and risks below). A true positive result means
that the test result is positive, and the condition or predisposition
is actually present. A true negative result means that the test result
is negative, and the condition or predisposition is not present. False
results can also be both positive and negative. A false positive occurs
when the test indicates a positive result when in fact the condition or
predisposition is not present. A false negative occurs when the test
indicates a negative result but the condition or predisposition is
present.
Potential benefits of a positive test result:
May provide knowledge of diagnosis or risk status.
May allow preventive steps or treatment interventions to
be taken.
May identify information about risk status in other family
members (also a potential harm).
Potential benefits of a negative test result:
May rule out specific genetic diagnosis or risk.
May eliminate the need for unnecessary screening or treatment.
Potential risks of a positive test result:
May expose individuals to unproven treatments.
May cause social, psychological and economic harms,
including stigmatization and potential exclusion from health insurance
and employment.
May identify information about risk status in other family
members (also a potential benefit).
For false positive test results, individuals may be
exposed to unnecessary screening and treatment.
Potential risks of a negative test result:
May give false reassurance regarding risk due to
nongenetic causes.
May have psychological effects, such as ``survivor guilt.''
For false negative test results, may delay diagnosis,
screening, and treatment.
Nature of health condition and health outcomes. The nature
(severity, degree of associated disability, or potentially stigmatizing
characteristics) of the health condition being tested for is an
important factor in assessing clinical utility. For example, a genetic
test for periodontal disease may raise less concern than a test for
cancer, and genetic tests developed for conditions such as alcoholism
or mental illness might cause even greater concern. Health outcomes, as
measured by such indicators as morbidity and mortality, are important
in assessing clinical utility of genetic testing, and they can be
affected by both the nature of the health condition as well as the
availability, nature, and efficacy of treatment. As uncertainties
increase about the health outcomes associated with a test result, so do
the potential harms of the test. This is an important consideration in
genetic testing for common health problems such as cancer and
cardiovascular disease, since health outcomes typically are the result
of the combined effects of genetic, environmental, and behavioral risk
factors.
Purpose of the genetic test. The purpose of the test is an
important factor in assessing clinical utility. Genetic tests used to
predict a disease or condition will have different risks and
uncertainties associated with it as compared to a diagnostic test. For
example, the use of a test to aid in the diagnosis of cystic fibrosis
in a person who has symptoms has different implications than the use of
a test to determine whether a woman with no symptoms has a risk for
breast and ovarian cancer because she possesses a BRCA1 or BRCA2
mutation. Tests used for diagnostic purposes will most likely be
conducted as part of a clinical evaluation to diagnose a specific
disease or will be used for clearly inherited diseases or conditions.
Genetic tests used for predictive purposes in healthy persons are
associated with greater uncertainties and risks. Currently, tests used
for predictive purposes will give an estimate of the risk a person may
have of developing a particular disease or condition. Due to incomplete
knowledge, however, the risk assessment may be inaccurate because of
other genetic and environmental factors that have not been accounted
for or are not yet known. Predictive genetic tests may have profound
effects on the lives of otherwise healthy individuals. Even though
degree of risk is uncertain, a positive test result for breast cancer
may affect treatment, reproductive, and lifestyle plans. A negative
test result for a BRCA1 mutation does not eliminate the risk of breast
cancer, because BRCA1 mutations account for only a small percentage of
breast cancer cases overall. A woman with a negative test result still
carries, at minimum, the breast cancer risk of the average woman and
she should still continue with preventive screening measures.
The use of a genetic test in population screening may raise greater
concern than the use of the same test in an individual seeking
information about his or her health. In population screening, a large
number of healthy people may receive unexpected test results that may
or may not provide definitive information. Decisions about whether to
use genetic tests for screening should take into account the prevalence
of the condition. The higher the prevalence of the genetic condition,
the greater the number of people who will be subjected to false
positive and false negative results. On the other hand, if treatment
options are available, screening for highly prevalent diseases may have
significant public health value.
Uncertainties of genetic test results. The assessment of a test's
clinical utility is affected by the accuracy of test results. False
negative results are more common in the early stages of the development
of diagnostic tests, including genetic tests. Genetic tests in early
development may identify only a portion of mutations associated with a
given health outcome. If a woman is from a family in which multiple
cases of early breast cancer have occurred, she is likely to be at risk
for an inherited susceptibility to breast cancer even if genetic
testing has failed to identify a specific cancer-associated mutation in
her family.
Information about family members. Because genetic information may
have implications for family members, the potential of the test to
reveal information about family members is another factor to be
considered in assessing a test's clinical utility. For example, DNA-
based tests for cystic fibrosis, sickle cell anemia, or other
conditions will identify carriers for the condition as well as those
who are affected. If a woman with breast cancer tests positive for a
BRCA1 mutation, her first-degree relatives are then known to have a 50
percent chance of carrying the same mutation. Some of these relatives
may not wish to discover their risk, while others may wish to use the
test
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results of their relatives to make a decision about their own genetic
testing.
Quality of evidence for outcomes assessment. The quality of
evidence for assessing outcomes of genetic test results is a factor in
the clinical utility of a genetic test. Often, evidence to assess
relevant factors, especially those related to potential social or
economic harms, is limited or lacking. In assessing potential risks
under these circumstances, incomplete information and the potential for
harms that have not yet been documented must be considered. Established
methods for evaluating the quality of the evidence should be used to
assess outcomes.
Factors To Be Considered in Assessing Social Issues
Important social considerations may heighten the risks of certain
tests, even if they are accurate and clinically meaningful. Tests for
certain health conditions may carry special risks because of the social
implications of the health condition, e.g., conditions associated with
mental illness or dementia. Thus, the social context of a disease may
be an important factor for an individual to consider prior to taking a
genetic test. In addition to affecting the individual, these special
risks may affect entire populations. In particular, special
consideration should be given to genetic stigmatization and
discrimination, genetic testing in specific U.S. populations, and the
possible development and use of genetic tests for non-health related
conditions.
Genetic stigmatization. Genetic test results can change how people
are viewed by their family, friends, and society, and how they view
themselves. People diagnosed with or at risk for genetic diseases or
conditions may be affected by the way others begin to see and interact
with them. Having or being at risk for a disease or condition that is
viewed by society in a negative light can result in stigmatization, and
emotional and psychological harms. In addition to changes in how they
are seen by others, social influences can affect self-perception and
have a profound impact on life decisions.
Genetic discrimination. Diagnostic or predictive genetic
information about an individual may lead to discrimination in health
insurance, life insurance, and education and employment. The potential
for discrimination may be particularly acute for people with, or at
risk for, diseases or conditions that are chronic, severely disabling,
and lack effective or affordable treatments. Educational opportunities
may be restricted, further limiting future life possibilities. Fears of
genetic discrimination have made the establishment of Federal privacy
and confidentiality protections a high priority for many.
As important as legal protections are, however, they cannot prevent
all adverse consequences of genetic information. For example, the
stigma associated with certain genetic diseases or conditions can
affect personal choices, such as marriage and child bearing.
Special considerations for U.S. populations. Significant social
concerns have grown out of the strong memories of the American eugenics
movement and the painful history of programs that tested minority
populations for conditions such as sickle cell disease. In some cases,
these programs heightened discrimination against those tested. Given
this history, tests developed for use in particular population groups,
whose incidence of a condition may be higher, or in circumstances where
the meaning of the test could be interpreted only within a certain
population, may carry higher risks. This issue is of great concern in
the United States because of the exceptional diversity of the
population. Specific genetic diseases or conditions occur with
different frequencies in different populations. As genetic testing
becomes more common, the potential for stigmatization of groups
increases. Educational programs, legal protections, and the involvement
of ethnocultural group representatives in assessing the risks and
benefits of genetic tests are needed to reduce the risk of
stigmatization of groups.
In addition, social categories used to classify ethnocultural
differences often do not accurately reflect actual genetic variation
within a population. For example, since the categories ``Hispanic'' and
``Asian'' encompass populations from different parts of the world,
genetic variations are likely to exist within these populations. Thus,
care should be taken in determining the ethnocultural background of
individuals in order to ensure accurate interpretation of genetic test
results. A further note of caution is also necessary. In developing
genetic tests, it will be important to assure their accuracy when used
in different populations. In so doing, however, the erroneous
assumption that there is a straightforward, one-to-one relationship
between one's genes and one's ethnocultural identity may be
inadvertently reinforced. This could result in stigmatization because
even accurate tests could reinforce misguided cultural notions about
genetic determinism.
Tests for conditions not commonly regarded as medical or health-
related. In the future, it may be possible to develop genetic tests
that could be used to identify predispositions to certain patterns of
behavior, such as risk-taking, shyness, or other complex features of
personality. Although the assumption that single genes, or even many
genes, can predict complex human actions is simplistic, the possibility
of such tests raises profound ethical questions and concerns because
their potential psychological and socioeconomic harms are so
significant and the potential misuse of such information is so great.
The boundaries between ``health-related'' and ``non-health related''
are not clear cut, and they may shift over time. It will, therefore, be
difficult to avoid harm from genetic tests simply by limiting their use
to situations of diagnosing or predicting disease. For example, genetic
tests might be used to predict susceptibility to conditions that are
health-related but where a strong behavioral component exists, such as
obesity, alcohol abuse, or nicotine addiction. Individuals identified
as at risk for stigmatized conditions such as these may suffer special
harms.
Questions Related to Issue 1:
1.1 What are the benefits/risks of having of a genetic test?
1.2 What are the major concerns regarding the different genetic
tests that are currently available?
1.3 What expectations do individuals have about genetic tests,
such as whether they have a high level of accuracy and can be used to
help make health or important personal decisions?
1.4 In deciding whether to have a genetic test, does it matter
whether a treatment exists for the condition or disease being tested
for? Is the information provided by the test important or useful by
itself?
1.5 Do concerns about the ability to keep genetic test results
confidential influence an individual's decision to have a genetic test?
1.6 Are genetic tests different from other medical tests, such as
blood tests for diabetes or cholesterol? Should genetic test results be
treated more carefully with more confidentiality than other medical
records?
Issue 2: How Can the Criteria for Assessing the Benefits and Risks of
Genetic Tests Be Used To Differentiate Categories of Tests? What Are
the Categories and What Kind of Mechanism Could Be Used To Assign Tests
to the Different Categories?
In attempting to address this issue, SACGT considered whether the
criteria
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of clinical validity and clinical utility could be used to characterize
the potential risks associated with a given test, which would allow
tests to be grouped according to the risks that are associated with
them. Using this information, tests might be organized into categories
such as ``high risk'' and ``low risk.'' Such a categorization would not
be simple or straightforward, however, because it would depend upon a
combination of factors, including test characteristics, availability of
safe and effective treatments, and the social consequences of a
diagnosis or identification of risk status. For example, a test of high
predictive value that identifies a nonstigmatizing condition with a
safe and effective treatment might fall into a low-risk category, while
a test that has high predictive value and that identifies a genetic
risk for a serious condition for which treatment is unproven might fall
into a high-risk category.
As these general examples illustrate, categorizing tests will
require the weighing of several different aspects of the test and of
the disease that the test is used to diagnose or predict. Developing an
appropriate mechanism for this process poses a challenge, and it is
likely that such a mechanism will involve at least three steps. In the
first step, data concerning the test would be collected perhaps using a
standardized format to ensure that all of the required data are
reported. In the second step, the data would be analyzed to determine
risk category. One possible approach would be to initially sort tests
into a readily identifiable low-risk category (possibly tests with
well-defined characteristics that meet a previously defined low-risk
threshold). For tests not falling within the low-risk category
(possibly tests for rare diseases or complex, common diseases), a third
step involving a more detailed evaluation of available data would be
required to make a final determination of risk category.
Thus, determining the risk category of a test will involve
evaluating the data available regarding the analytical and clinical
validity of the test and the outcomes of positive and negative test
results. This evaluation should consider socioeconomic factors, such as
the potential for stigmatization and other social risks, including the
likelihood that a test would be used in particular population groups.
For tests that are determined to be high risk or potentially high risk,
the analysis likely will require a diverse range of technical expertise
and input.
Questions Related to Issue 2:
2.1 Do some genetic tests raise more ethical, legal, medical, and
social concerns than others and should they be in a special category
and require some special oversight? If so, what tests or types of tests
would fall into such a category?
2.2 Are there some genetic tests that raise no special concerns
and therefore need no special oversight? If so, what tests or types of
tests would fall into this category?
Issue 3: What Process Should Be Used To Collect, Evaluate, and
Disseminate Data on Single Tests or Groups of Tests in Each Category?
Currently, data about genetic tests are collected by a number of
different organizations. Some of these data are publicly available;
others are not. It appears that in the future, a laboratory that
develops a particular test will need to continuously collect data
regarding its analytical validity, and at a minimum, a summary of the
results of the evaluation should become available as part of the
information on analytical validity contained in the test labeling.
Data on clinical application of a test could be collected and
evaluated by a number of sources, including professional organizations,
individual laboratories, academic institutions, and/or governmental
agencies. One option is to continue to rely on the current practice of
allowing laboratories to base decisions on information they collect and
analyze, including their own data or data they glean from other
sources, such as research publications or consensus conferences. A
second option is to make each laboratory that offers a test responsible
for collecting and analyzing the information that is required to
support its claims for the test according to national standards. A
third choice would be for a Government agency, possibly the CDC, to
coordinate the creation and collection of information on clinical
applications of tests that detect particular mutations and perhaps to
define appropriate claims for tests as well. (See Part IV for a
discussion of CDC's current efforts in this area.) A fourth option,
discussed as part of Issue 4, would be to form a consortium of
government, professional associations, and industry that would create,
collect, and analyze information about clinical applications. More than
likely, data on any genetic test will be incomplete and must be
collected on a continuous basis. If the data available at the time of
the initial evaluation suggest benefit of the test in clinical
practice, the test may be approved on the condition that data will
continue to be collected and will be reviewed again at a future date.
Another approach to data collection on validity and utility of
genetic tests could be modeled after tumor registries. Tumor registries
document and store information about a patient's history, diagnostic
findings, treatment, and outcome. Information within a tumor registry
may be used to generate a variety of reports on topics such as patient
quality of care and long-term results of specific treatments.
Regardless of the option chosen for data collection, once the data
have been collected and evaluated, they must be disseminated to health
care practitioners and the public. This must include not only data
generated prior to offering the test for clinical use, but also data
generated as part of any postmarket evaluation. One option is to
require laboratories to release summaries of data on clinical
application as part of the process of offering the test. Such summaries
could be directed to health care professionals, to the general public,
or to both. In addition, different methods of collection and
distribution of information may be used for different tests. Guidelines
or regulations might be required to make those distinctions. One method
would be to rely upon publications and professional societies to inform
readers and members, with the expectation that practitioners will
inform the public over time. Alternatively, the Federal Government or a
consortium could be responsible for ensuring that relevant data are
available for both professional and public use.
Questions Related to Issue 3:
3.1 Given that collection of data is an ongoing process, what type
of system or process should be established to collect, evaluate, and
disseminate data about the analytical validity, clinical validity and
clinical utility of genetic tests?
3.2 How can the system or process for data collection, evaluation,
and dissemination be structured in such a way as to protect the privacy
and confidentiality of the data that is collected?
Issue 4: What Are the Options for Oversight of Genetic Tests and the
Advantages and Disadvantages of Each Option?
SACGT has been asked to focus on oversight of the accuracy and
effectiveness of genetic tests--especially, the development, use, and
marketing of genetic tests developed by clinical laboratories. SACGT
recognizes that there are many areas beyond test development, use, and
marketing that might have an equally important impact in assuring the
safety and effectiveness of a genetic test. For example, the
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training and education of health care providers who prescribe genetic
tests and use their results for clinical decision making is a critical
issue, in particular as it relates to their ability to stay abreast of
new information on the uses, capabilities, and limitations of these
tests. The effect that gene patenting is having on the cost,
accessibility, and quality assurance of genetic tests is another
critical issue, as is the potential for workplace and insurance
discrimination that could result from genetic testing. Oversight of
genetic tests that provide non-health related information is another
area of inquiry. SAGCT will focus its attention on these other high
priority oversight issues once it completes its current work.
Current Oversight of Genetic Tests
As a starting point, it is important to recognize that some
oversight of the development, manufacturing, use, and marketing of
genetic tests is already in place. Currently, genetic and nongenetic
tests receive the same level of oversight from governmental agencies.
These oversight provisions are discussed in Part III and reiterated
here briefly. All laboratory tests, including genetic tests, performed
for the purpose of providing information for the health of an
individual must be conducted in laboratories certified under CLIA. The
CLIA program provides oversight through inspections conducted by HCFA
using its own scientific surveyors or surveyors of deemed organizations
or State-operated CLIA programs that have been approved for this
purpose. The oversight provided includes a comprehensive evaluation of
the laboratory's operating environment, personnel, proficiency testing,
quality control, and quality assurance. To date, CLIA oversight has
emphasized intra-laboratory processes. As discussed in Part IV, HCFA
and CDC have taken steps to develop recommendations for more specific
requirements for the performance of genetic tests under CLIA.
Under the medical device regulations, the FDA requires that genetic
tests packaged and sold as kits to laboratories require premarket
approval or clearance by the FDA. The premarket review would evaluate
the test's accuracy and analytical validity. For devices in which the
link between clinical performance and analytical performance has not
been well established, the FDA requires that additional analyses be
conducted to determine the test's clinical characteristics, or its
clinical sensitivity and specificity. In some cases, the FDA requires
that the predictive value of the test be analyzed for positive and
negative results. The FDA has not attempted to extend its authority to
regulate home brew tests (tests developed by laboratories for their own
use). All of the genetic tests described in Part II are home brew
tests. FDA has implemented regulation of the active ingredients of
genetic tests, or analyte-specific reagents (ASRs). Manufacturers of
ASRs are required to comply with good manufacturing practices,
restriction of sales to laboratories capable of performing complex
tests, and requirements that certain information accompany both the
reagents and the test results.
Additional oversight protections are provided by professional
organizations and state health departments. Organizations such as CAP,
ACMG, and NCCLS have developed guidelines and standards for the
development and use of genetic tests. State health departments may
require laboratory facilities and personnel that perform genetic tests
be licensed.
Possible Areas of Oversight
In considering areas of oversight, SACGT has focused on several key
issues. While these are not the only areas in which additional
oversight might be considered, and public comment on other issues would
be welcome, SACGT expects to consider at least the following issues.
Introducing Laboratory-Developed Tests into Clinical Practice.
Analytical Validity. It seems clear that a genetic test should not be
used in clinical practice (i.e., for other than research purposes)
unless it has been shown to detect reliably the mutation that it is
intended to detect. CLIA now requires a laboratory that offers a test
to determine the analytical validity of the test before it is used in
clinical practice. In the current system, the laboratory intending to
offer a test decides when it has met CLIA's requirement, a judgment
that may later be audited during a CLIA inspection. Most believe that
the current system needs review. Some have suggested that voluntary or
mandatory standards should be enhanced to assist laboratories in
deciding when a test's analytical validity has been determined and is
acceptable, or that laboratories should be required to obtain the
concurrence of an independent third party before a test is offered for
use in clinical practice.
Clinical Validity. Similar questions arise with respect to the
appropriate level of knowledge about a test's ability to generate
information about the presence, or possibility of future occurrence, of
a disease. Determining a genetic test's clinical validity is a complex
and usually long term process (often requiring decades of work). At the
same time, many people want to see gene discoveries translated into
practical use as soon as the discoveries are made, often before the
clinical validity of the test is fully established. The use of the test
is then refined as new information becomes available. No Federal
standards guide laboratory decision making with respect to when enough
is known about a genetic test for it to be used in clinical practice or
the extent to which uncertainties about a test's characteristics must
be disclosed.
Clinical Utility. Also important is the degree to which benefits
are provided by positive and negative test results. Some have argued
that genetic tests should not be available unless they can provide
information useful in making health-related decisions and that
consumers are likely to assume that a test would not be made available
unless it has a health benefit. For example, a negative genetic test
result may provide a useful basis of information for informed decision-
making. Others have argued that access to information, even it if does
not lead to an health-related intervention, is itself useful. There is
currently no requirement that the clinical utility of a genetic test be
assessed before it is used in clinical practice, and some observers
have suggested that additional oversight is needed to ensure greater
awareness of the utility of the test.
Changes in Test Methodology. When test manufacturing methods and
materials change, either deliberately or inadvertently, the performance
characteristics of a test can change as well, which can change the
analytical validity, clinical validity, and clinical utility of the
test. Some have suggested that stronger incentives should be created to
re-qualify tests when methods and materials change.
Patient Safeguards. Informed consent in the research phase of
development. In some cases, laboratories that are developing genetic
tests for eventual use in clinical practice conduct studies using
identifiable patient samples. Unless the study is conducted with
Federal funding or is intended for submission to FDA, there is no
Federal requirement that laboratories obtain informed consent from a
patient participating in that study.
Informed consent for tests used in clinical practice. Even after a
test has been accepted into clinical practice, some observers have
suggested that due to the predictive power of genetic tests and the
impact test results may have on the individual and their families,
tests
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should not be administered unless the individual has been fully
informed of the test's risks and benefits and a written informed
consent obtained. There is currently no requirement for such an
informed consent.
Availability of genetic education and counseling. Current oversight
does not specifically address whether genetic education and qualified
counseling should be made available for all genetic tests. Genetic test
results may be difficult to interpret and present in an understandable
manner, raise important questions related to disclosure of test results
to family members, and sometimes involve difficult treatment decisions.
Because of these intricate issues, some have suggested that those who
offer genetic tests should be encouraged or required to make genetic
education or counseling available to individuals.
Post Market Data Collection. Many tests are put into clinical use
before full information about their validity and utility has been
obtained. Virtually everyone agrees that it is critical that data
continue to be collected after such tests reach the market. Yet, no
comprehensive method for data collection now exists. Many observers
believe that ongoing mechanisms to collect data need to be put in
place. A number of potential mechanisms to accomplish data collection
are outlined in the discussion of Issue 3.
Information Disclosure and Marketing. Data disclosure. There is no
current requirement that data about a test's analytical validity,
clinical validity, or clinical utility, or lack thereof, be disclosed
to health care providers or patients. Some observers believe that
laboratories should be encouraged or required to make such information
available and to ensure that the data is accurate and complete.
Promotion and marketing. Although the Federal Government requires
that promotion and marketing of products and services (which sometimes
takes the form of educational materials), be truthful and not
deceptive, Federal agencies have taken little enforcement action
against false or deceptive claims involving genetic tests. While some
believe that false or deceptive claims are not currently a problem,
others have suggested that promoting or advertising genetic tests,
especially to patients/consumers, should be prohibited. Another
suggestion is that promotion and advertising of genetic tests may be
permitted, but emphasis should be placed on taking action against false
or deceptive claims.
Possible Directions and Implications of Further Oversight
SACGT welcomes public input on whether further oversight measures
are needed, and if so, how additional oversight might be addressed. If,
from its deliberations and public consultation, SACGT determines that
further oversight is needed, possible directions that could be taken
include the strengthening and expansion of current CLIA or FDA
regulations or voluntary standards and guidelines, the formation of
interagency review boards, or the formation of a consortium of
representatives from government, industry, and professional
organizations.
In assessing whether further oversight is warranted, it is
important to consider the implications that further oversight may have
on the current system and all parties involved. Among other issues, any
new proposals to provide additional oversight of this rapidly growing
technology should take into consideration the trade-offs involved as
well as the evolving nature of genetic research and technology.
Trade-offs. In considering whether additional oversight is
warranted, the risks, benefits, and economic implications (both short
and long term) associated with oversight must be considered. More
stringent oversight, for example, may ensure greater certainty that a
test has been shown to be accurate and useful, that patient safeguards
are in place, and that health care dollars are not spent on tests of
little value. On the other hand, additional oversight may delay the
introduction of new tests (or improvements to existing tests) into
clinical practice and increase the costs of test development, which may
in turn discourage the development of new tests. The provision of any
type of additional oversight is likely to have resource implications
that may affect the costs of genetic tests and public access to them.
Evolving nature of genetic research and technology. New information
on genetics and human diseases and conditions are published on an
almost daily basis, and new technologies are emerging rapidly. Due to
this pace of discovery and technological change, the assessment of the
analytic validity, clinical validity, and clinical utility of a genetic
test is likely to change in light of new findings. For example, data
from population studies or the identification of additional genes or
mutations will change and, in most cases, improve knowledge about a
specific genetic disease or condition in a specific population.
Observers have suggested that laboratories will need to be able to
access and assimilate new information continuously in order to update
the clinical validity and utility of their tests and that oversight
methods will need to monitor, guide, and sample the flow of new
information rather than take snapshots of what is known at a given
moment in time. According to this view, health care providers and
oversight groups will need to recognize and adapt their methods to the
conditions created by continuous knowledge generation.
Questions Related to Issue 4:
4.1 Information about the accuracy, validity, and usefulness of
genetic tests is being gathered through research studies. At what point
should an experimental test be considered ready for general use? Is it
important for a test to be immediately available even if its validity
has not been fully established? Might the point at which a test is
considered ready for general use be different for different types of
genetic tests? Since data on the validity of tests for rare diseases
are especially difficult to collect, should special considerations be
given to rare disease testing to ensure access to these tests and, if
so, what should the considerations be?
4.2 What level of confidence should individuals have, or might
they want to have, in the information they receive about a genetic
test? Would the level of confidence change depending on the type of
disease (e.g., cancer versus gum disease) or the type of testing being
done (e.g., predictive versus diagnostic testing)?
4.3 Is making information available to the consumer about a
genetic test, such as information about its accuracy, predictive power,
and available therapy, a sufficient form of oversight?
4.4 Would one form of oversight be to review or inspect
promotional material directed to consumers (such as commercials,
billboards, or Internet marketing) and health care providers (such as
package inserts) to make sure that claims made are accurate? Is this
sufficient oversight?
4.5 Should genetic education/counseling provided by an individual
with special training always be available when genetic tests are
offered? Should this apply for every genetic test or only for some
kinds of genetic tests?
4.6 Certain trade-offs may be necessary in order to ensure that
genetic tests are safe and effective. Are consumers willing to pay for
the cost of additional oversight of genetic tests (in the form of
higher prices, health insurance premiums, or taxes)? Are consumers
willing to wait for the effectiveness of genetic tests to be
[[Page 67289]]
demonstrated before having access to a new genetic test?
Issue 5: What Is an Appropriate Level of Oversight for Each Category of
Genetic Test?
Different levels of oversight may be appropriate for tests that
present different or unknown levels of risk, have different purposes,
and are at different stages of development. Until SACGT has had an
opportunity to consider public comment, it is premature for SACGT to
formulate or offer any views on whether additional oversight is needed,
and if so, what form it should take. SACGT welcomes public comment on
this subject.
Question Related to Issue 5:
5.1 How can oversight be made flexible enough to incorporate and
respond to rapid advances in knowledge of genetics?
Issue 6: Are There Other Issues in Genetic Testing of Concern to the
Public?
6.1 Is the public willing to share, for research purposes, genetic
test results and individually identifiable information from their
medical records in order to increase understanding of genetic tests?
For example, tumors removed during surgery are often stored and used by
researchers to increase understanding of cancer. Should samples from
individuals with genetic disorders or conditions be managed in a manner
similar to cancer specimens? Or does the public feel that this could
cause confidentiality problems? If so, are there special informed
consent procedures that should be used?
6.2 Research studies involving human subjects or identifiable
human tissue samples that are funded by the Government or are subject
to regulations of the FDA must be reviewed by an Institutional Review
Board (IRB). (An IRB is a specially constituted review body established
or designated by an organization to protect the welfare of human
subjects recruited to participate in biomedical or behavioral
research.) Some studies involving genetic tests do not fall into either
of these categories and, therefore, are not required to be reviewed by
an IRB. For example, a private laboratory developing a test for its own
use would not be required to obtain IRB review. Should all experimental
genetic tests be required to be reviewed by an IRB?
6.3 When some medical tests (e.g., routine blood counts) are
performed, patients do not sign a written consent to have the test
performed. Should health care providers be required to obtain written
informed consent before proceeding with a genetic test? Should this
apply to all tests or only certain tests? Should testing laboratories
be required to obtain an assurance that informed consent has been
obtained before providing test services?
6.4 Does the public support the option of being able to obtain a
genetic test directly from a laboratory without having a referral from
a health care provider? Why or why not?
6.5 Should any additional questions or issues be considered
regarding genetic testing?
Part VI. Conclusion
SACGT was chartered to advise the DHHS on the medical, scientific,
ethical, legal, and social issues raised by the development and use of
genetic tests. At SACGT's first meeting in June 1999, the Assistant
Secretary for Health and Surgeon General asked the Committee to assess,
in consultation with the public, whether current programs for assuring
the accuracy and effectiveness of genetic tests are satisfactory or
whether other measures are needed. This assessment requires
consideration of the potential benefits and risks (including
socioeconomic, psychological, and medical harms) to individuals,
families, and society, and, if necessary, the development of a method
to categorize genetic tests according to these benefits and risks.
Considering the benefits and risks of each genetic test is critical in
determining its appropriate use in clinical and public health practice.
The question of whether more oversight of genetic tests is needed
has significant medical, social, ethical, legal, economic, and public
policy implications. The issues may affect those who undergo genetic
testing, those who provide tests in health care practice, and those who
work or invest in the development of such tests. SACGT is endeavoring
to encourage broad public participation in the consideration of the
issues. Such public involvement in this process will enhance SACGT's
analysis of the issues and the advice it provides to DHHS. SACGT looks
forward to receiving public comments and to being informed by the
public's perspectives on oversight of genetic testing.
Comment Period and Submission of Comments
In order to be considered by SACGT, public comments need to be
received by January 31, 2000. Comments can be submitted by mail or
facsimile. Members of the public with Internet access can submit
comments through email or participate in the SACGT website
consultation.
Secretary's Advisory Committee on Genetic Testing, National
Institutes of Health, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892, 301-496-9839 (facsimile), [email protected] (email),
http://www4.od.nih.gov/oba/sacgt.htm (website).
Dated: November 24, 1999.
Sarah Carr,
Executive Secretary, SACGT.
[FR Doc. 99-31226 Filed 11-30-99; 8:45 am]
BILLING CODE 4140-01-P