[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,

[[Page 67278]]

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

[[Page 67279]]

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

[[Page 67280]]

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

[[Page 67281]]

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

[[Page 67282]]

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

[[Page 67286]]

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

[[Page 67288]]

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