[Federal Register Volume 65, Number 76 (Wednesday, April 19, 2000)]
[Notices]
[Pages 21094-21109]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-9808]



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Part IV





Department of Health and Human Services





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Secretary's Advisory Committee on Genetic Testing; Notice of Meeting

  Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / 
Notices  

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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 
Preliminary Final Recommendations 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). The 
meeting will be held from 8:45 a.m. to 5:00 p.m June 5, 2000 to June 7, 
2000 at the Governor's House Hotel, 1615 Rhode Island Avenue, NW, 
Washington, DC 20036. In addition to completing its report on 
oversight, the Committee will also be exploring the impact of gene 
patenting and restrictive licensing on the cost, quality, and 
accessibility of genetic testing, Federal regulatory requirements 
regarding informed consent in genetic research involving information-
gathering about family members, and genetics education of health 
professionals. The meeting will be open to the public, with attendance 
limited to space available. Individuals who wish to provide public 
comment on the oversight recommendations of genetic tests or other 
issues should contact Susanne Haga at 301-496-9838. A draft agenda will 
be posted at the following website address http://www4.od.nih.gov/oba/sacgt.htm prior to the meeting.
    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 of and use of genetic tests. SACGT is 
presently assessing the adequacy of current oversight of genetic 
testing in the United States, in consultation with the public. After 
careful analysis of the issues and an effort to gather and consider 
public comments, SACGT drafted preliminary conclusions and 
recommendations on oversight of genetic tests. It is now seeking 
further public comments on these preliminary conclusions and 
recommendations. The preliminary recommendations will also be posted on 
SACGT's website and sent to groups and individuals who submitted 
comments in the prior comment period.
    The public is encouraged to submit written comments on this 
preliminary report by May 22, 2000. SACGT's mailing address is: SACGT, 
National Institutes of Health, 6000 Executive Blvd., Suite 302, 
Bethesda, Maryland 20892. SACGT's facsimile number is 301-496-9839. 
Comments can also be sent via e-mail to [email protected]. All public 
comments received will be available for public inspection at the SACGT 
office between the hours of 8:30 a.m. and 5:00 p.m. Questions about 
this request for public comment can be directed to Susanne Haga, Ph.D., 
Program Analyst, SACGT, by e-mail ([email protected]) or telephone (301-
496-9838).

Adequacy of Oversight of Genetic Tests

Preliminary Conclusions and Recommendations of the Secretary's Advisory 
Committee on Genetic Testing

Executive Summary

    The Secretary's Advisory Committee on Genetic Testing (SACGT) was 
chartered in 1998 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. In June 1999, Dr. 
David Satcher, Assistant Secretary for Health and Surgeon General, 
asked SACGT to assess, in consultation with the public, the adequacy of 
oversight of genetic tests and, if warranted, based on a consideration 
of the public comments and an analysis of the issues, to recommend 
options for additional oversight and to ensure public access to quality 
genetic tests. Dr. Satcher asked the Committee to report back by March 
15, 2000, and to organize its report around five major issues:
     What criteria should be used to assess the benefits and 
risks of genetic tests?
     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?
     What process should be used to collect, evaluate, and 
disseminate data on single tests or groups of tests in each category?
     What are the options for oversight of genetic tests and 
the advantages and disadvantages of each option?
     What is an appropriate level of oversight for each 
category of genetic test?
    SACGT worked intensely through the summer and fall of 1999 to 
design a multifaceted process to gather public comments on genetic 
testing oversight issues. The public consultation process was carried 
out during a 60-day period from December 1, 1999, to January 31, 2000, 
and involved a Federal Register notice, a targeted mailing to 2,500 
individuals and organizations, a website consultation, and a public 
meeting that was held on January 27, 2000. In addition, SACGT conducted 
a literature review and analysis of scholarly articles on genetic 
testing.
    On February 24-25, 2000, SACGT met to review public comments 
received and to develop recommendations on the adequacy of oversight of 
genetic testing. SACGT carefully reviewed the public input received, 
which highlighted the importance of ensuring the quality of, and access 
to, genetic tests. In addition, many of the public comments expressed 
concern about the potential for genetic test results to be used to 
discriminate against people in areas such as employment and health 
insurance. After considering the public comments, SACGT developed the 
following preliminary overarching principles and recommendations.
Overarching Principles
     One of the main goals of genetic testing is to improve the 
health and well-being of individuals and families. No test should be 
introduced in the market before it is established that it can diagnose 
and/or predict a health-related condition accurately and safely. Thus, 
the public is best served by ensuring both the appropriate oversight of 
genetic tests and the continued development of genetic tests.
     The public, through involvement of advocacy groups, 
organizations, and individuals, needs to be involved in the ongoing 
consideration of issues surrounding genetic testing. This will be 
particularly important in addressing the concerns of minority 
populations and diverse communities regarding the purposes and uses of 
genetic testing.
     Since genetic education and counseling are critical to the 
appropriate use, interpretation, and understanding of genetic test 
results, efforts to ensure the education of the public and of health 
providers about genetics are necessary.
     Federal legislation is needed to prohibit discrimination 
in employment and health insurance based on genetic information. 
Federal legislation is also needed to protect the privacy of genetic 
information in medical records. Without these protections, the public 
will be reluctant to undergo genetic tests that might be beneficial to 
its health and well-being.
Recommendations
    Issue 1: What criteria should be used to assess the benefits and 
risks of genetic tests?
     Analytical validity, clinical validity, clinical utility, 
and social issues should be the major criteria used

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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?
     For the purposes of review, a useful way to consider tests 
is to assess them across several dimensions. These criteria are 
necessary but may not be sufficient for all tests.
     Is the test at this stage of development primarily 
diagnostic or predictive?
     Is the mutation being tested for highly or weakly 
penetrant?
     Is a proven intervention available to prevent or treat the 
disease for which the test is being conducted?
     Is the test used for population-based screening or testing 
of individuals?
     Is the prevalence of the disorder for which the test is 
used high or low?
     Is there potential for stigmatization of individuals or 
groups from the test results?
     Is the test designed or able to identify more than one 
condition?
    For example, predictive tests require more scrutiny than do 
diagnostic tests. Similarly, tests for weakly penetrant mutations 
require more assessment than do those for highly penetrant genes. Tests 
for conditions for which no interventions are available would be more 
problematic than tests for conditions for which interventions exist. 
Thus, for example, a high-scrutiny test would be one that is 
predictive, detects a mutation that is weakly penetrant, and for which 
a proven intervention is not available. These dimensions should be 
considered in the review of genetic tests, and test developers should 
indicate the categories into which their test(s) fit.
    Issue 3: What process should be used to collect, evaluate, and 
disseminate data on single tests or groups of tests in each category?
     The responsibility for collecting initial data on the 
analytical validity of a test lies with the test developer.
     Initial knowledge of the clinical validity of a genetic 
test is essential to assess its safety and efficacy. Further knowledge 
will depend on additional research and the long-term systematic 
collection and analysis of additional data. Researchers and test 
developers should gather and share initial data on the clinical 
validity and utility of genetic tests.
     Since data sharing and analysis are critical, relevant 
DHHS agencies should work collaboratively with researchers and test 
developers to advance data collection and provide this information to 
health care providers and the public. Initial exploratory data 
collection efforts among DHHS agencies, which have been coordinated by 
the Centers for Disease Control and Prevention, have been of value and 
should continue.
     Protecting the confidentiality of data and the privacy of 
individuals is essential to the progress of data collection efforts.
     Laboratories should be encouraged or required to make pre- 
and post-marketing data on genetic tests available in a timely, 
accurate, and understandable manner.
     Post-market data collection can enhance understanding of 
current applications of a genetic test and is important for any 
expansion of the use of a genetic test beyond the initial indications 
approved when the test is made available. Laboratories providing 
clinical genetic services should commit to post-market data collection 
efforts.
    Issue 4: What are the options for oversight of genetic tests and 
the advantages and disadvantages of each option?
     Based on the rapidly evolving nature of genetic tests, 
their anticipated widespread use, and extensive concerns expressed by 
the public about their potential for misuse or misinterpretation, 
additional oversight is warranted for all genetic tests.
     The Food and Drug Administration (FDA) should be the lead 
federal agency responsible for reviewing, approving, and labeling of 
all new genetic tests. FDA review should focus on the claims of 
analytical and clinical validity made by the developer of the test and 
be appropriate to the level of scrutiny warranted by the test. The 
agency should develop flexible mechanisms for review of new genetic 
tests that minimize both the time and the cost of review without 
jeopardizing the quality of the assessment of test validity. These 
mechanisms should, for example, include the use of deemed reviewers and 
standards developed in concert with professional organizations.
     Clinical Laboratory Improvement Amendment regulations 
should be augmented to provide more specific provisions for ensuring 
the quality of laboratories conducting genetic tests.
     DHHS agencies should be provided with sufficient resources 
to carry out expanded oversight of genetic tests, including coordinated 
data collection, review, and information dissemination.
    Issue 5: What is an appropriate level of oversight for each 
category of genetic test?
     Institutional Review Board review should be conducted of 
all research protocols for genetic tests in which individually 
identifiable human subjects or samples are used, regardless of the 
funding source. Institutions that lack an IRB must obtain the services 
of a qualified board. Efforts will be needed to ensure that IRBs are 
suitably equipped to carry out these reviews. In addition, informed 
consent must be obtained from all subjects participating in such 
research.
     FDA should give particular attention to the review of 
genetic tests that are used to predict diseases and conditions for 
which no safe and effective interventions are available. Other tests 
may also warrant a higher level of scrutiny in the FDA review process.
     In the future, tests may be developed that raise major 
social and ethical concerns. Because FDA's review will focus on 
assuring the analytical and clinical validity of a test, the agency's 
capacity to assess the ethical and social implications of a test may 
not be sufficient. The Secretary should consider the development of a 
mechanism to ensure the identification, and appropriate review, of 
tests that raise major social and ethical concerns.
     The U.S. Preventive Services Task Force with augmented 
resources, or a similar body set up or given deemed status for this 
purpose, should review genetic tests that are already on the market for 
evaluation of clinical efficacy and development of guidelines about 
their appropriate use.
Additional Recommendations for the Appropriate Use of Genetic Tests
     Individual and family members considering a genetic test 
should have access to appropriate genetic education and counseling 
resources to ensure their ability to make an informed decision about 
being tested.
     Written informed consent should be obtained for tests used 
for predictive purposes. The extent to which written informed consent 
should be obtained for all other genetic tests requires further 
deliberation.
     Current regulations under FDA and the Federal Trade 
Commission should be enforced in the area of genetic test promotion and 
marketing.
    On March 15, 2000, SACGT forwarded preliminary recommendations to 
Dr. Satcher. At this time, the Committee invites public comment on this 
preliminary draft of its conclusions and recommendations, and at its 
next meeting, June 5-7, 2000, the Committee will review the comments 
received and will then develop a final

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report to the Secretary. With the completion of this assignment, SACGT 
will move on to consider a number of other high-priority issues raised 
by genetic tests that are not the subject of this report.

Adequacy of Oversight of Genetic Tests

Preliminary Conclusions and Recommendations of the Secretary's Advisory 
Committee on Genetic Testing

Introduction

    The Secretary's Advisory Committee on Genetic Testing (SACGT) was 
chartered in June 1998 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 National Institutes of Health 
(NIH)-Department of Energy (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, Dr. David Satcher, 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 
and, if warranted, to recommend options for additional oversight.
    Dr. Satcher provided SACGT with a framework of five central 
questions around which to organize the assessment and requested that 
SACGT report back by March 15, 2000. During the summer and fall of 
1999, the Committee gathered background information on genetic testing, 
designed five approaches to gather professional and public opinions on 
oversight of genetic testing, and prepared a document for soliciting 
public comment. The public consultation was held from December 1, 1999, 
to January 31, 2000. On February 24-25, 2000, the Committee met to 
review the public input received and to develop conclusions and 
recommendations on the adequacy of oversight of genetic testing. SACGT 
submitted a brief report of its preliminary recommendations to Dr. 
Satcher on March 15, 2000.
    This report presents for public comment SACGT's preliminary 
conclusions and recommendations. Public comments will be reviewed at 
SACGT's next meeting, June 5-7, 2000, after which the Committee will 
submit its final conclusions and recommendations to the Secretary.

Background

    Decades of genetics research have brought about many important 
medical and public health advances. The pace of discovery in this area 
has enabled scientists to make rapid progress in understanding the role 
of genetics in many common yet complex diseases and conditions, such as 
heart disease, cancer, and diabetes. It also has increased knowledge 
that may lead to the development of new tests to identify these disease 
conditions in individuals, sometimes before symptoms occur.
    Genetic testing involves the analysis of chromosomes, DNA, RNA, 
genes, and/or gene products to determine whether an alteration is 
present that is causing or is likely to cause a specific disease or 
condition. Genetic tests can be performed for a number of purposes. 
Moreover, a test can be used in more than one way. For example, a test 
used for diagnostic purposes could also be used to predict risk of 
disease.
     Preimplantation diagnosis is used following in vitro 
fertilization to diagnose a genetic disease or condition in a 
preimplantation embryo.
     Prenatal diagnosis is used to diagnose a genetic disease 
or condition in a developing fetus.
     Newborn screening is performed in newborns in state public 
health programs to detect certain genetic diseases for which early 
diagnosis and treatment are available.
     Carrier testing is performed to determine whether an 
individual carries one copy of an altered gene for a particular 
recessive disease. The term ``recessive'' refers to diseases that will 
occur only if both copies of a gene that an individual receives have a 
disease-associated mutation; thus, each child born to two carriers of a 
mutation in the same gene has a 25-percent risk of being affected with 
the disorder.
     Diagnostic/confirmatory testing is used to identify or 
confirm the diagnosis of a disease or condition in an affected 
individual. Diagnostic testing may also be useful to help determine the 
course of a disease and choice of treatment.
     Presymptomatic testing is used to determine whether 
individuals who have a family history of a disease but no current 
symptoms have the gene alteration associated with the disease.
     Predictive testing determines the probability that a 
healthy individual with or without a family history of a certain 
disease might develop that disease.
    In the past, many tests were developed to detect or confirm rare 
genetic diseases. More recently, tests have been developed to detect 
mutations that may be involved in or contribute to more common, complex 
conditions (such as breast, ovarian, and colon cancer and 
cardiovascular disease), the effects of which generally do not appear 
until later in life. Optimally, these tests are used to predict a 
person's predisposition to disease where there is a family history of 
the disease. In general, such tests are not recommended for individuals 
without a family history of the disease.
    The process of discovering and understanding genetic mutations and 
their role in disease is extremely complex and can involve many years 
of investigation. In addition, because the genome is vast, discovering 
a specific disease-related gene has, up to now, been a difficult and 
time-consuming process. Nevertheless, the development and clinical use 
of genetic tests is expected to increase rapidly over the next decade, 
driven in large part by research funded and conducted by agencies 
within DHHS, especially NIH, as well as by work in the private sector. 
The Human Genome Project, a major international collaborative effort 
established and supported by public groups, including NIH and DOE, is 
expected to have a major impact on gene discovery and genetic test 
development. The results of the Human Genome Project, along with new 
technical advances, such as tandem mass spectrometry, microarrays, and 
gene chips, will speed the pace of disease gene discovery.
    Once the entire sequence of the human genome has been determined, 
scientists will have a critical tool 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 the effects of 
confounding factors such as gene-gene interactions and environmental 
influences (smoking and diet, for example). A full understanding of the 
role of genetic mutation in the current and future health of 
individuals will require more research, ranging from detailed 
biochemical studies to population-based studies that focus on 
clarifying and elucidating the significance of how genes interact with 
each other and with the environment.
    A rising new area in medicine is pharmacogenomics, the combination 
of the fields of genomics and pharmacology that builds on the work of 
the Human Genome Project. Much of human variation is due to small 
differences in a person's DNA, referred to as single nucleotide 
polymorphisms (SNPs). Pharmacogenomics is the

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application of genetic science and technology to understand how these 
genetic variations influence responses to medicines. Because 
individuals may not react in the same way to a given drug, 
understanding the correlation between a person's unique SNPs and his or 
her drug response will be of great benefit. This knowledge will help 
health professionals determine a person's likely response to a medicine 
before it is prescribed. Other potential benefits of pharmacogenomics 
include the development of effective therapies, prescribed with less 
trial and error, and the ability to target beneficial drugs and reduce 
adverse drug reactions.
    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.\i\ A recent survey of genetic 
testing laboratories found that over a three-year period, the total 
number of genetic tests performed increased by at least 30 percent each 
year, rising from nearly 100,000 in 1994 to more than 175,000 in 
1996.\ii\
    In 1997, the NIH-DOE Task Force on Genetic Testing'charged to 
review genetic testing in the United States and to make recommendations 
to ensure the development of safe and effective genetic tests--
concluded that although genetic testing was developing successfully in 
the United States, some concerns about it exist.\iii\ The Task Force 
grouped the concerns into four major categories: (1) The manner in 
which tests are introduced into clinical practice; (2) the adequacy and 
appropriate regulation of laboratory quality assurance; (3) the degree 
of understanding of genetics on the part of health care providers, 
patients, and the public; and (4) the continued availability and 
quality of testing for rare diseases.
    A number of the Task Force recommendations were aimed at enhancing 
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 and made suggestions about the need for additional data and 
external review of genetic tests. While recommending that revisions to 
the current review process may be needed to assess the effectiveness 
and usefulness of genetic tests, the Task Force did not specify how the 
review of laboratory-based genetic tests should be changed.
    DHHS established SACGT to help the nation prepare for some of the 
revolutionary changes in clinical and public health practice resulting 
from the continued and increasing use of genetic testing. SACGT builds 
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.
    It is critical for the public to understand that while genetic 
tests can be extremely beneficial, they also can pose risks, including 
medical and psychological risks, risks to families, and social and 
economic risks that may affect entire groups as well as individuals. As 
the diagnostic and predictive uses of genetic testing continue to 
increase, and as the effects of testing on society become clearer, its 
impact will become broader and ultimately will affect all of our lives. 
Because the use and ramifications of these tests are not yet fully 
realized, additional consideration is needed regarding whether current 
programs for assuring the safety and effectiveness of genetic tests are 
satisfactory or whether additional oversight measures are needed before 
such tests are introduced for wide-scale use.

Charge to the Committee

    SACGT was asked to frame its recommendations around the following 
five issues:
     What criteria should be used to assess the benefits and 
risks of genetic tests?
     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?
     What process should be used to collect, evaluate, and 
disseminate data on single tests or groups of tests in each category?
     What are the options for oversight of genetic tests and 
the advantages and disadvantages of each option?
     What is an appropriate level of oversight for each 
category of genetic test?
    The level of oversight of genetic tests has significant medical, 
social, ethical, legal, economic, and public policy implications. 
Because the system of oversight can 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--SACGT 
actively sought public input on the five questions listed above. The 
Committee concluded that to fully respond to its charge, it was 
especially important to reach out to diverse communities that might 
have particular concerns about genetic testing and members of the 
public who have not yet undergone genetic testing, but are likely to 
face decisions about these tests in the future.
Public Consultation Process
    SACGT employed several mechanisms for gathering public comment and 
assessing the status of prior debate about the issues surrounding 
genetic testing. A Federal Register notice, a targeted mailing to 
interested individuals and organizations, a web-based consultation, and 
a public meeting provided several venues in which the public could 
submit comments.iv To provide a framework for receiving 
input on the five questions in the Committee's charge, SACGT developed 
a document, A Public Consultation on Oversight of Genetic Tests, which 
provided background information about genetic tests, including their 
current limitations, benefits and risks, and provisions for oversight 
currently in place. A summary of the consultation document was prepared 
in English and Spanish.
    SACGT received nearly 400 comments from the general public, health 
professionals, individuals and families affected with genetic 
conditions, religious groups, state health departments, industry, 
professional organizations, academia, and patient advocacy 
organizations. The comments were analyzed qualitatively with respect to 
the five specific issues SACGT was asked to address. (Because the 
comments were not a representative sample of the U.S. population, no 
attempt was made to perform statistical analysis.) SACGT was enormously 
impressed with the effort people made to participate in this process 
and believes that its recommendations are strengthened and enriched by 
the views, opinions, and perspectives the public has shared.
    As part of its effort to gather broad-based perspectives on the 
oversight of genetic testing, SACGT also conducted a literature review 
and analysis of more than 70 published scholarly articles on genetic 
testing. Most of the articles were published within the last five years 
and were written by professionals in the fields of law, science, and 
bioethics.

Characteristics of Genetic Tests and Implications for Oversight

    Genetic tests currently have certain limitations that are relevant 
to the issue of oversight.v 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

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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 an 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. In 
addition, the frequency of common cystic fibrosis mutations varies 
among population groups.
Complexity of Human Disease
    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 absolute 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 or ovarian cancer. 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 other genetic and environmental factors.
Gap Between Diagnosis and Treatment
    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 not be available for 
some time--a situation sometimes called the ``therapeutic gap.'' 
However, while knowledge that a disease or condition will or could 
develop may not provide any direct clinical benefit, it may lead to 
increased monitoring that 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, that 
information can also lead to discrimination or other forms of misuse of 
personal genetic information.
The Changing Nature of Genetic Information
    In addition to the limitations of genetic tests, information 
provided by genetic tests also has potential benefits and risks. 
Understanding the benefits and risks of a genetic test to individuals 
or particular populations, which may change over time as more 
information is gathered, is critical in determining its appropriate use 
in clinical and public health practice. As further research is 
conducted and knowledge gained, the validity of test results may 
increase or decrease.
Potential Benefits of Genetic Tests
    Individuals with a family history of a disease live with 
uncertainties about their own lives as well as their children's futures 
that may be relieved by having a genetic test. For example, if the test 
result is positive, it can provide an opportunity for psychological 
counseling and for the introduction of risk-reducing interventions, 
such as regular screening practices and healthier lifestyles. Early 
interventions (such as annual colonoscopies to check for precancerous 
polyps, the earliest signs of colon cancer) could help prevent deaths 
from colon cancer. If the test result is negative (the mutation is not 
present), 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 also 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 who have two copies of a certain 
gene do not respond to a drug used in some Alzheimer's patients. 
vi In individuals with the disease who do not have both 
copies of that gene, however, the drug seems to slow progression of the 
disease.
Potential Risks of Genetic Tests
    However, at the same time that genetic tests offer great potential 
benefits, they can also pose risks. Genetic testing poses potential 
physical, medical, psychological, and social and economic 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 cause miscarriage in 1 in 200 to 400 
cases.
    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. For 
example, individuals with positive test results may choose not to have 
children or 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. Substantial risks are posed by 
incorrect test results or the misinterpretation of test results. False 
negative test results can mean delays in diagnosis and treatment, while 
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 and emotional 
risks. Predictive testing of healthy individuals may have significant 
psychological and social impacts. The knowledge about disease risk may 
prove burdensome because of uncertainty about how to manage risk when 
data about the efficacy or preventive measures is constantly changing, 
such as controversies about dietary interventions or the use of hormone 
replacement therapy in preventing heart disease.
    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 may have 
developed a 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 for escaping a disease that others in the family 
have developed (known as survival guilt). A

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negative test result may provide a false sense of security because an 
individual may not understand that even with a negative test result, he 
or she still bears 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 child tests positive for 
sickle cell trait (having one copy of the sickle cell gene) during 
newborn screening, it implies that one of the parents is a carrier. It 
is also possible for genetic tests to inadvertently disclose 
information about a child's parentage.
    Genetic test results can pose risks for groups if they lead to 
stigmatization of that group and discrimination of its members. 
Concerns about the potential risks of discrimination and 
stigmatization, based on information gained from genetic testing are 
particularly acute among groups who have experienced genetic 
discrimination in the past and other forms of discrimination.
    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 that also have a behavioral component, such as alcohol 
abuse, nicotine addiction, or eating disorders, 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, social and economic harms are so significant and the 
potential misuse of such information is so great. Because of these 
complexities, SACGT focused its discussions on the use of genetic tests 
to determine health-related information about individuals and/or 
families.

Current System of Oversight of Genetic Tests

    As part of its charge, SACGT reviewed the provisions for oversight 
of genetic tests already in place. Currently, government agencies 
accord genetic and nongenetic tests the same level of oversight. 
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, the Federal Policy for the 
Protection of Human Subjects (45 CFR part 46, 21 CFR part 50, and 21 
CFR part 56).
    Four DHHS organizations have roles in the oversight of genetic 
tests: the Centers for Disease Control and Prevention (CDC), the Food 
and Drug Administration (FDA), the Health Care Financing Administration 
(HCFA), and the Office for Protection from Research Risks (OPRR). 
Although they do not have regulatory functions, NIH, the Health 
Resources and Services Administration (HRSA), and the Agency for 
Healthcare Research and Quality (AHRQ) support research activities and 
demonstration projects that generate knowledge about and experience 
with genetics and genetic testing. In addition, some states regulate 
genetic tests, and some professional organizations have issued relevant 
guidelines for professional practice.
The Roles of CDC and HCFA
    All laboratory tests performed for the purpose of providing 
information about the health of an individual must be conducted in 
laboratories certified under CLIA. 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, 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 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 surveyors of deemed organizations or state-operated CLIA 
programs approved for this purpose. This oversight includes a 
comprehensive evaluation of the laboratory's operating environment, 
personnel, proficiency testing, quality control, and quality assurance. 
The laboratory director plays a critical role in assuring the safe and 
appropriate use of laboratory tests. The laboratory director must meet 
the required CLIA qualifications for laboratory director and must 
ensure that the test methodologies selected are capable of providing 
the quality of results required for patient care. Laboratory directors 
are required to take specific actions to establish a comprehensive 
quality assurance program, as outlined by CLIA, that 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 analysis and 
reporting of the results), CLIA oversight has emphasized intra-
laboratory processes as opposed to the clinical uses of test results.
    CLIA has not specifically outlined in its current review processes 
additional aspects of oversight that are critical to the appropriate 
use of genetic tests, such as clinical validity and clinical utility. 
Also unaddressed are the issues of informed consent for clinical 
genetic testing after the research phase and adequate access to genetic 
counseling to assure the appropriate transfer of information. HCFA and 
CDC are taking steps to develop more specific laboratory requirements 
for genetic testing under CLIA, including provisions for the pre- and 
post-analytical phases of the testing process, and CDC will be issuing 
a Notice of Intent in the Federal Register to gather public comment on 
the proposed changes to CLIA.
    Through its Office of Genetics and Disease Prevention, CDC also has 
a role in addressing the public health impact of advances in genetic 
research, furthering the collection, analysis, dissemination, and use 
of peer-reviewed epidemiologic information on human genes and 
coordinating the translation of genetic information into public health 
research, policy, and practice. CDC is also leading an interagency 
effort to explore how voluntary, public/private partnerships might help 
encourage and facilitate the gathering, review, and dissemination of 
data on the clinical validity of genetic tests. Two pilot data 
collection efforts, one for cystic fibrosis and one for hereditary 
hemochromatosis, are in the preliminary stages.
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 pre-market approval or clearance by FDA. This pre-market review 
involves an analysis of the device's accuracy as well as its analytical 
sensitivity and specificity. Pre-market review is performed based on 
data submitted by sponsors to scientific reviewers in the Division of 
Clinical Laboratory Devices in FDA's

[[Page 21100]]

Office of Device Evaluation. In addition, for devices for which the 
link between clinical performance and analytical performance has not 
been well established, FDA requires that additional analyses be 
conducted to determine the test's clinical characteristics, that is, 
its clinical sensitivity and specificity. In some cases, 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 and are being provided as clinical laboratory services. 
These tests are referred to as in-house tests or ``home brews.'' FDA 
has stated that it has authority, by law, to regulate such tests, but 
the agency has elected as a matter of enforcement discretion to not 
exercise that authority, in part because the number of such tests is 
estimated to exceed the agency's current review capacity.
    However, 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.
    With few exceptions, however, the current regulatory process does 
not require a pre-market 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 performing high-complexity tests and requires that certain 
information 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. In 1999, FDA established the Molecular and Clinical 
Genetics Panel of the Medical Devices Advisory Committee to serve as a 
source of independent advice in the area of DNA-based diagnostics.
The Role of Regulations Protecting Human Subjects
    Additional oversight is provided during the research phase of 
genetic testing if the research involves human subjects or identifiable 
samples of their DNA. OPRR and FDA administer regulations governing the 
protection of human research subjects. OPRR oversees the protection of 
human research subjects in DHHS-funded research. FDA oversees the 
protection of human research subjects in trials of investigational (not 
yet approved) 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, to review and approve the informed consent process, and 
to evaluate whether risks 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 FDA has elected not to 
exercise its enforcement authority. CLIA requirements apply to DHHS-
funded research only if the results of the genetic test are used for 
patient care, meaning that results are provided to a subject, to the 
subject's family, or to the subject's health care provider. OPRR 
regulations would apply if the laboratory was funded by DHHS or was 
conducting research at an institution that receives DHHS funding.
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 subject 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. NIH also 
produces consensus statements and technology assessment reports on 
issues important to health care providers, patients, and the general 
public. Topics related to genetic testing have included the development 
and assessment of newborn screening for sickle cell disease, genetic 
testing for cystic fibrosis, and screening for and management of 
phenylketonuria (PKU).
The Role of AHRQ
    As the lead federal agency in health care quality, AHRQ is expected 
to play a greater role in promoting research on optimal methods of 
organizing, delivering, and financing genetic services and measuring 
the impact of these factors on the quality of patient care. AHRQ now 
plays an important role in making better health-related information 
available to health plans, purchasers of health care, clinicians, and 
patients, and in developing methods for facilitating shared patient-
physician decision-making. In particular, the agency has developed an 
instrument (Consumer Assessment of Health Plans, or CAHPS) that allows 
consumers to assess their current health plan and a website that 
catalogues clinical practice guidelines. The Technology Assessment 
Program of the agency has a role in rigorously evaluating the 
beneficial and adverse outcomes associated with health care 
interventions (both diagnostic and therapeutic) in order to inform 
consumers, health professionals, and payors. AHRQ also supports the 
U.S. Preventive Services Task Force, which rigorously reviews evidence 
for the effectiveness of more than 100 interventions to prevent 
illnesses and conditions, including screening tests for genetically 
determined conditions such as PKU and Down Syndrome, and recommends 
which of these interventions clinicians should provide to their 
patients.
The Role of HRSA
    The mission of HRSA is to assure access to health care, including 
genetic services, for those who are medically underserved. Access is 
attained through a broad range of programs including support for 
community health centers, maternal and child programs, health 
professional training programs, and state public health agency 
infrastructure (Maternal and Child Health Block Grants). The Genetic 
Services Program of HRSA promotes support and leadership for assurance, 
assessment and policy development for utilization of genetic medicine 
and technology within health care and public health practice. In this 
role, HRSA has supported the development and quality assurance of 
screening tests for PKU, congenital hypothyroidism, and sickle cell 
anemia and for the management of these conditions within the health 
care setting and within newborn screening programs. In addition, HRSA 
has provided funding to assist public health systems develop genetic 
medicine and technology and demonstration projects

[[Page 21101]]

related to the translation of genetic technology into practice. With a 
special focus on underserved populations, these programs have evaluated 
how genetic tests are used in practice and have identified barriers to 
access and use.
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 and 
California, 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 state newborn screening laboratories must meet the requirements 
of CLIA's quality control and proficiency testing programs, but in 
general there is little Federal oversight of their programs. State 
newborn screening laboratories and many commercial laboratories that 
perform testing for state newborn screening programs have used the 
National Newborn Screening Quality Assurance Program for verifying test 
accuracy and for meeting CLIA quality assurance requirements. This is 
particularly important because of the absence of a requirement for 
HCFA-approved proficiency testing programs for newborn screening.
The Role of the Private Sector
    Recognized professional organizations provide oversight in 
voluntary partnership with HCFA and CDC, some of which serve as agents 
for the government in accreditation activities. These groups also 
develop 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 following:
     the College of American Pathologists (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 standards for test 
methodologies;
     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; and
     COLA, a nonprofit, physician-directed, national 
accrediting organization whose purpose is to promote excellence in 
medicine and patient care through programs of voluntary education, 
achievement, and accreditation.
    Other organizations, such as the American Academy of Pediatrics, 
the American College of Obstetrics and Gynecology, the American Society 
of Human Genetics, and the National Society of Genetic Counselors, are 
also involved in the development of guidelines and recommendations 
regarding the appropriate use of genetic tests. Patient advocacy 
groups, as well as individuals and families affected with genetic 
conditions, also play an important role in setting standards and in 
developing guidelines through advocacy and monitoring of health care 
practices.

Conclusions and Recommendations

    SACGT was asked to assess 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 social, economic, 
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.
    Genetic tests offer great promise and provide hope for many people 
who wish to improve the health of their families and themselves. At the 
same time, if introduced prematurely or applied inappropriately, the 
outcomes of genetic testing could place some individuals and groups at 
risk. Thus, an important balance must be struck between the need to 
encourage the development and dissemination of new tests and the need 
to ensure that their introduction yields more benefit than harm.
    SAGCT was guided by a recurrent theme that emerged from the public 
comments. Although many citizens believe that the risks and potential 
benefits of genetic tests are no different than those posed by any 
other type of medical test, there is a widespread perception that these 
tests are different and that people experience genetic testing in a way 
that is dissimilar to the experience of other forms of medical testing.
    Comments received from the public by SACGT highlighted lingering 
and persistent concerns about the risks of inappropriate disclosure of 
genetic information about individuals and the potential that such 
disclosure would result in stigma and discrimination. One individual 
wrote that the public ``will not be able to utilize fully the promise 
of genetic testing without assurances of the privacy of test results 
and safeguards against discrimination in health care and employment.''
    Based on these and other concerns, SACGT arrived at several 
overarching principles that address public concerns and relate to the 
establishment of enhanced oversight.
     One of the main goals of genetic testing is to improve the 
health and well-being of individuals and families. No test should be 
introduced in the market before it is established that it can diagnose 
and/or predict a health-related condition accurately and safely. Thus, 
the public is best served by ensuring both the appropriate oversight of 
genetic tests and the continued development of genetic tests.
     The public, through involvement of advocacy groups, 
organizations, and individuals, needs to be involved in the ongoing 
consideration of issues surrounding genetic testing. This will be 
particularly important in addressing the concerns of minority 
populations and diverse communities regarding the purposes and uses of 
genetic testing.
     Since genetic education and counseling are critical to the 
appropriate use, interpretation, and understanding of genetic test 
results, efforts to ensure the education of the public and of health 
providers about genetics are necessary.
     Federal legislation is needed to prohibit discrimination 
in employment and health insurance based on genetic information. 
Federal legislation is also needed to protect the privacy of genetic 
information in medical records. Without these protections, the public 
will be reluctant to undergo genetic tests that might be beneficial to 
its health and well-being.
    In addition to developing these basic principles, SACGT considered 
each of the five questions in its charge separately, recognizing that 
there is tremendous overlap in the issues raised under each question. 
The Committee's conclusions and recommendations are based on its 
analysis of the public input received, the literature reviewed, and 
discussions held on these issues at each of its four public meetings.

[[Page 21102]]

    Issue 1. What criteria should be used to assess the benefits and 
risks of genetic tests?
     Analytical validity, clinical validity, clinical utility, 
and social considerations should be the major criteria used to assess 
the benefits and risks of genetic tests.
    SACGT identified four criteria'analytical validity,vii 
clinical validity,viii clinical utility,ix and 
societal issues--that can be used to assess the benefits and risks of a 
genetic test. The importance of these criteria was confirmed in the 
public comment process. Assessing the potential benefits and risks of a 
genetic test 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.
Analytical Validity
    Analytical validity is an indicator of how well a test measures the 
property or characteristic it is intended to measure. In a DNA-based 
test, an analytically valid test would be positive when the particular 
gene mutation is present (analytical sensitivity) and negative when the 
gene mutation is absent (analytical specificity). A key measure of a 
test's analytical validity is its accuracy, or the probability that the 
measured value will be within a predefined range or the true activity 
or level. Another measure of analytical validity is reliability, or the 
probability of repeatedly getting the same test result. 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.
    While the analytical validity of a test must be determined, it is 
not a sufficient criterion for assessing the potential benefits and 
risks of a test. Members of the public noted that the availability of 
treatment options or the opportunity for prevention or amelioration of 
disease through lifestyle change are key requirements in assessing 
benefits and that in the absence of such interventions, benefits 
diminish. It is important to remember, however, that for some 
individuals, knowledge of a condition--even without options for 
prevention or treatment--can be of value. The possibility that a 
genetic test can resolve uncertainty is an important benefit for some 
individuals. Conversely, some individuals find value in not knowing the 
results of a test for which no intervention is available.
Clinical Validity and Utility
    Once the analytical validity of a test is established, the second 
step in assessing the benefits and risks of a genetic test is to 
evaluate how well it performs in the clinical environment. This 
involves evaluating a test's clinical validity and clinical utility. 
Clinical validity refers to the accuracy of the test in diagnosing or 
predicting risk for a health condition and is measured by the 
sensitivity, specificity, and predictive value of the test for a given 
health condition. Clinical utility involves identifying the outcomes 
associated with positive and negative test results. Because the 
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.
    Thus, in considering a system for assessing benefits and risks, it 
is crucial to recognize that only individuals can weigh the balance 
between negatives and positives once a test is deemed safe and 
efficacious and that not everyone will make the same choice. 
Participants at the public meeting stated that one of the major 
benefits of genetic testing is that it enables patients to make 
informed medical decisions and life choices. One participant summed up 
this view by noting that ``Individuals expect a high level of accuracy 
and to be able to use the genetic information obtained to make medical 
or personal decisions.''
    The complexity of the interpretation of a test result is a critical 
determinant of risk, and the contribution of other genetic factors as 
well as environmental factors to disease development can complicate the 
interpretation of a test result. The more complex the interpretation, 
the greater the possibility for harm. For example, a test might be 
clinically valid and useful in one population, but not in another. Or, 
a test might be appropriate for use in adults, but not in newborns. In 
addition, genotype/phenotype correlations vary within a given disease 
category, even for single gene disorders.
    An important distinction in considering the risks and potential 
benefits of a test is that between the technical aspects of a given 
test--that is, its clinical validity and utility--versus how it is 
interpreted by health care providers and the individuals undergoing 
testing. A clinically valid test in the hands of a poorly trained 
health care provider can pose as much risk as a less valid or accurate 
test that is correctly interpreted. A clinically valid test 
administered to individuals without involving them in an informed 
decision-making process can also pose considerable risk to that 
individual or family. Thus, one way to minimize harms is to ensure that 
tests are administered by qualified professionals and that appropriate 
education and genetic counseling is provided.
    Individuals submitting comments to SACGT frequently mentioned the 
need for health care providers to demonstrate competence in 
understanding the information and its implications, and a number of 
individuals suggested that availability of and access to genetic 
counseling would reduce the public's concerns about genetic testing. 
One commenter noted that the issues of benefits and risks are ``the 
reason that genetic counseling and evaluation is so necessary for 
genetic testing.'' In addition, one private laboratory that offers 
genetic testing services stated that ``many of the questions we receive 
from client health care providers and patients relate to the 
translation and interpretation of genetic information in our medical 
reports.'' In fact, commenters often mentioned that inadequate public 
understanding and physician education are causes of the confusion and 
risks associated with genetic testing. One commenter urged ``more 
emphasis * * * on improving the education and influencing the attitudes 
of health professionals regarding genetic matters.'' Participants in 
the public meeting also emphasized the importance of education in 
minimizing the potential harms of genetic testing and in maximizing its 
potential benefits to diverse communities.
Factors to Be Considered in Assessing Clinical Validity
    A test's clinical validity is influenced by a number of factors, 
including the purpose of the test, the prevalence of the disease or 
condition for which the test is being conducted, and the adequacy of 
the information available to determine clinical validity.x 
Genetic tests have a number of purposes, and some are used for more 
than one purpose. The acceptable level of the predictive value of a 
genetic test may vary depending on the purpose for which the test is 
used (for example, for diagnosing a condition in a person with symptoms 
or for predicting a future health risk in an otherwise asymptomatic 
individual).xi In addition, a higher predictive value may be 
required of a test for which no

[[Page 21103]]

other confirmatory test or clinical measure is available.
    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.
    For many genetic tests, particularly those that are predictive or 
presymptomatic, 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 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 psychological, social, 
and economic consequences of testing as well as the implications for 
health outcomes. Decisions about the use of a genetic test should be 
based upon a consideration of the risks of any follow-up tests required 
to confirm an initial positive test, the efficacy of available 
treatments, the degree of certainty with which a diagnosis can be made, 
and the potential for adverse psychological and social and economic 
effects versus beneficial treatment if a diagnosis is made. Factors 
affecting clinical utility include (1) the purpose of the test; (2) the 
quality of evidence for assessing outcomes; (3) the potential benefits 
and risks of test results; (4) the nature of the health condition and 
its potential outcomes; (5) uncertainties of genetic test results; and 
(6) the provision of information concerning other family members.
Purpose of the Test
    As in assessing clinical validity, the purpose of the test is an 
important factor in assessing clinical utility. Different risks and 
uncertainties are associated with genetic tests that are used to 
predict a future disease or condition than with those that are used for 
diagnostic purposes. For example, the use of a test for a specific 
mutation 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 has a BRCA1 or BRCA2 mutation that might alter her 
risks. Tests used for diagnostic purposes will most likely be conducted 
as part of a clinical evaluation to diagnose a specific disease, or 
they will be used for diseases or conditions that are clearly 
inherited.
    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, because the higher the prevalence of the genetic 
condition, the greater the number of people who may receive unnecessary 
treatment or false reassurance if the test produces false positive or 
false negative results. On the other hand, if treatment options are 
available, screening for highly prevalent conditions may have 
significant public health value.
The Quality of the Evidence for Assessing Outcomes
    The quality of evidence for assessing outcomes of genetic test 
results is a factor to consider in determining the clinical utility of 
a genetic test. Often, the evidence needed to assess clinical utility 
is limited or lacking. Established methods for evaluating the quality 
of the evidence should be used to assess outcomes. (Issues pertaining 
to data collection and analysis are addressed more fully in Issue 3, 
below.)
Potential Benefits and Risks
    A number of potential benefits and risks of genetic testing can be 
associated with positive or negative test results. For example, 
potential benefits of a positive test result include the possibility 
that it may provide knowledge of diagnosis or risk status, it could 
allow preventive steps or treatment interventions to be taken, or it 
may identify information about risk status in other family members 
(also a potential harm). The potential benefits of a negative test 
result include ruling out a specific genetic diagnosis or risk and/or 
eliminating the need for unnecessary screening or treatment.
    The potential risks of a positive test result include exposure of 
individuals to unproven treatments; potential for social, 
psychological, and economic harms, including altered self-image, impact 
on family relationships, stigmatization, and potential exclusion from 
health insurance and employment; and identification of risk status in 
other family members (also a potential benefit). For false positive 
test results, individuals may be exposed to unnecessary screening or 
treatment. A negative test result could give false reassurance 
regarding risk due to nongenetic causes or induce psychological effects 
such as survivor guilt. False negative test results may delay 
diagnosis, screening, and treatment.
The Nature of the Health Condition
    In determining the relative risks and benefits of a given test, 
these outcomes also must be considered in light of the nature 
(severity, degree of associated disability, or potentially stigmatizing 
characteristics) of the disorder being tested for, which 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 because of possible 
misuse of such information. 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. The greater the uncertainty about the health 
outcomes associated with a test result, the greater 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.
Uncertainties of Genetic Test Results
    Genetic tests used to predict a specific disease or condition in 
otherwise healthy persons are associated with greater uncertainties and 
risks than are those used to diagnose a disease or condition. 
Currently, tests used for predictive purposes will provide an estimate 
of a person's risk of developing a particular disease or condition. 
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. Even so, predictive genetic tests may have profound effects 
on the lives of otherwise healthy individuals.
    False negative results are more common in the early stages of the 
development of diagnostic tests,

[[Page 21104]]

including genetic tests. Genetic tests in early development may 
identify only a portion of mutations associated with a given health 
outcome. The role of other genetic and environmental factors is still 
unknown for many conditions and will also affect the certainty of 
genetic test results.
Implications for Family
    Because genetic information may have implications for relatives of 
the individual being tested, the potential of the test to reveal 
information about family members or to alter interfamilial 
relationships are additional factors 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 an 
individual tests positive for Huntington's disease, 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 results of their relatives 
to make a decision about their own genetic testing.
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, for example, conditions 
associated with mental illness or dementia. Thus, some dimensions of 
genetic testing may affect society as a whole and certain social groups 
as well as individuals, and this requires that special consideration be 
given to the potential for further stigmatization and discrimination of 
members of vulnerable or at-risk groups.
    Genetic test results can change how people are viewed by their 
family, friends, and society as well as how people 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.
    Diagnostic or predictive genetic information about an individual 
could lead to discrimination in health insurance, life insurance, 
education, and employment, a fear expressed repeatedly in public 
comments to SACGT. The fear of discrimination may be particularly acute 
for people with or at risk for diseases or conditions that are chronic 
and severely disabling and that lack effective or affordable 
treatments. Educational opportunities may be restricted, further 
limiting life possibilities. Fears of genetic discrimination have made 
the establishment of federal privacy and anti-discrimination 
protections a high priority for many. In addition to concern about 
discrimination, there may be downstream effects of a transformation in 
medicine to a focus on predicting future disease risks that are not yet 
fully understood.
    Significant social concerns have grown out of painful memories of 
the American eugenics movement and the more recent history of programs 
that tested African Americans for sickle cell disease and disadvantaged 
populations for ``feeble-mindedness.'' Because these programs 
heightened discrimination against those tested, tests developed for use 
in certain targeted population groups may carry higher risks.
    In addition, because social categories used to classify 
ethnocultural differences often do not accurately reflect actual 
genetic variation within a population, care should be taken to ensure 
accurate interpretation of genetic test results by obtaining, to the 
extent possible, accurate knowledge regarding the ethnocultural and/or 
genetic background of the individuals being tested. A further note of 
caution is also necessary. In developing genetic tests, it will be 
important to ensure that they are accurate when used in different 
populations, even though doing so may inadvertently reinforce the 
erroneous assumption that there is a straightforward, one-to-one 
relationship between one's genes and one's ethnocultural identity, 
possible resulting in stigmatization. Even accurate tests can reinforce 
misguided cultural notions.
    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?
    SACGT considered whether analytical validity, clinical validity, 
clinical utility, and social issues could be used to characterize the 
potential benefits and risks associated with a given test. Using this 
information, SACGT suggested in the public consultation document that 
tests might be organized into categories such as ``high risk'' and 
``low risk,'' while acknowledging that this would not be a simple or 
straightforward task. Categorization would depend on the consideration 
of 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. In 1975, 
the National Academy of Sciences recommended that genetic tests be 
considered in terms of three categories, based on the complexity and 
usefulness of the information to the individual being 
tested.xii
    The difficulty of arriving at a straightforward schema was 
reflected in the public comments received. Some individuals suggested 
categorizing genetic tests by the purpose of the test, such as newborn 
screening, prenatal, carrier, predictive, or diagnostic testing. Others 
suggested categorizing tests by the availability of treatment or 
preventive measures, by the demonstration of clinical validity, or by 
the stage of development of the test.
    A number of public commenters believed that certain genetic tests 
raise more ethical, legal, and social concerns than do others. In this 
category, they identified prenatal, presymptomatic, and predictive 
tests, especially when no treatment measures are available. Commenters 
viewed diagnostic and confirmatory tests and tests for diseases for 
which treatment is available as raising less concern.
    Additional considerations for the level of review of genetic tests 
include gene frequency--that is, whether the test would be for a common 
or an orphan (rare) disease; whether the test will be used for 
population-based screening or individual testing; the potential for 
stigmatization of individuals or groups; and the availability of 
independent methods of confirmation to reduce the occurrence of false-
positive test results.
    For the purposes of review, a useful way to consider tests is to 
assess them across several dimensions. These criteria are necessary but 
may not be sufficient for all tests.
     Is the test at this stage of development primarily 
diagnostic or predictive?
     Is the mutation being tested for highly or weakly 
penetrant? xiii
     Is a proven intervention available to prevent or treat the 
disease for which the test is being conducted?
     Is the test used for population-based screening or testing 
of individuals?
     Is the prevalence of the disorder for which the test is 
used high or low?

[[Page 21105]]

     Is there potential for stigmatization of individuals or 
groups from the test results?
     Is the test designed or able to identify more than one 
condition?
    For example, predictive tests require more scrutiny than do 
diagnostic tests. Similarly, tests for weakly penetrant mutations 
require more assessment than do those for highly penetrant genes. Tests 
for conditions for which no interventions are available would be more 
problematic than tests for conditions for which interventions exist. 
Thus, for example, a high-scrutiny test would be one that is 
predictive, detects a mutation that is weakly penetrant, and for which 
a proven intervention is not available. These dimensions should be 
considered in the review of genetic tests, and test developers should 
indicate the categories into which their test(s) fit.
    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. While some of these data are publicly 
available, others are not. 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. Inherent in any extension 
of data collection requirements is an added burden to the delivery 
system as well as an added cost for provision of health care. These are 
important considerations that must be carefully understood and 
resolved.
    SACGT considered many options for collection, evaluation, and 
dissemination of data on genetic tests, including the following:
     Continuing reliance 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.
     Requiring that each laboratory that offers a test be 
responsible for collecting and analyzing the information that is 
necessary to support its claims, according to national standards.
     Establishing that a government agency take primary 
responsibility for collecting information on clinical applications of 
tests that detect particular mutations and defining the appropriate 
claims for such tests.
     Forming a consortium of government, professional 
associations, and industry to create, collect, and analyze information 
about clinical applications.
    Regardless of the option chosen for data collection, once the data 
have been collected and evaluated, they must be disseminated in an 
appropriate manner to health care practitioners and the public. One 
public commenter stated that ``the public needs to be informed about 
general information that evolves from the data about genetic tests, at 
the same time as the practitioners are informed.'' Others suggested 
that information should be easily accessible by all and recommended an 
Internet-based database system. One commenter supported ``the concept 
of developing peer reviewed Internet resources that provide information 
on genetic tests for health providers and the public.''
    SACGT concludes that databases on genetic tests should include not 
only data generated prior to offering the test for clinical use, but 
also data generated as part of any post-market evaluation. One option 
for dissemination 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.
    Through the public comment process, SACGT learned that the issues 
of privacy and confidentiality of data collected for research is a 
major concern of individuals participating in such studies. One 
commenter noted that ``collection of data to establish analytic and 
clinical validity is severely compromised by fear of discrimination.'' 
Many individuals indicated that they would be willing to share genetic 
test results and individually identifiable information if informed 
consent were obtained and assurances of confidentiality were provided. 
Many commenters recommended that data collected for research should be 
anonymized or coded to protect the privacy and confidentiality of the 
individual and the data. Participants at the public meeting suggested 
that individuals involved in research studies should receive feedback 
on the outcomes and findings of the study. Others have suggested that 
there are risks involved in receiving investigational tests results 
before the meaning of the information is understood.
     The responsibility for collecting initial data on the 
analytical validity of a test lies with the test developer.
     Initial knowledge of the clinical validity of a genetic 
test is essential to assess its safety and efficacy. Further knowledge 
will depend on additional research and the long-term systematic 
collection and analysis of additional data. Researchers and test 
developers should gather and share initial data on the clinical 
validity and utility of genetic tests.
     Since data sharing and analysis are critical, relevant 
DHHS agencies should work collaboratively with researchers and test 
developers to advance data collection and provide this information to 
health care providers and the public. Initial exploratory data 
collection efforts among DHHS agencies, which have been coordinated by 
the Centers for Disease Control and Prevention, have been of value and 
should continue.
     Protecting the confidentiality of data and the privacy of 
individuals is essential to the progress of data collection efforts.
Need for Post-Market Data Collection and Dissemination
    SACGT believes that it is critical that data continue to be 
collected after genetic tests reach the market. In addition, there is 
no current requirement that data about a test's analytical validity, 
clinical validity, or clinical utility, or lack thereof, should be 
disclosed to health care providers or patients. BRCA1 is an example of 
a test that should have been released with disclaimers about the 
limited knowledge about the test's clinical validity, which was based 
on data from a small and highly selected group of families in which 
multiple cases of cancer had occurred. Better post-market data 
collection and analysis will allow for expansion of the use of the test 
after it has been proven and understood in the initial target 
population. There should be some assurance that additional data will be 
collected after a test is preliminarily approved, using some minimal 
standards, and that data will be continuously reported, so that at any 
given point in time the level of knowledge about any test is sufficient 
and that for a selective few tests, more intensive studies are needed.
     Laboratories should be encouraged or required to make pre- 
and post-marketing data on genetic tests available

[[Page 21106]]

in a timely, accurate, and understandable manner.
     Post-market data collection can enhance understanding of 
current applications of a genetic test and is important for any 
expansion of the use of a genetic test beyond the initial indications 
approved when the test is made available. Laboratories providing 
clinical genetic services should commit to post-market data collection 
efforts.
    Issue 4: What are the options for oversight of genetic tests and 
the advantages and disadvantages of each option?
    Oversight of genetic tests can occur through multiple approaches. 
SACGT identified a number of possible directions that could be taken to 
improve oversight of genetic tests, including (1) strengthening and 
expanding current CLIA or FDA regulations or voluntary standards and 
guidelines; (2) forming interagency review boards; or (3) forming a 
consortium of representatives from government, industry, and 
professional organizations.
    In assessing whether further oversight is warranted, SACGT 
emphasized the importance of considering the implications that further 
oversight may have on the current system and all parties involved as 
well as the trade-offs and the evolving nature of genetic research and 
technology. SACGT also recognized that there are many areas beyond test 
development, use, and marketing, such as the training and education of 
health care providers and public understanding of genetics that might 
have an equally important impact on assuring the safety and 
effectiveness of a genetic test.
    The public comments were evenly divided between favoring a greater 
federal role in oversight versus forming a public/private consortium 
that would be responsible for oversight. Commenters noted the 
advantages of a consortium, including flexibility and broad 
representation of stakeholders. The advantages of a greater federal 
role cited in public comments are increased resources, centralization 
of oversight, and the provision of rigorous standards. Some commenters 
specifically recommended FDA as the federal agency of choice to oversee 
genetic tests. One said that ``FDA should use the authority it has to 
regulate all genetic tests and any kits that might be developed as part 
of gene sequencing.'' Others suggested that strengthening current CLIA 
regulations was preferable. Still others favored integrating all three 
approaches, with expansion of a consortium approach integrated with 
enhanced roles for FDA oversight of test validity and expanded CLIA 
oversight of testing practices, including enforcement of requirements 
for pre- and post-analytical test functions. Participants in the public 
meeting suggested that oversight should not be limited to the tests 
themselves, but should also apply to the manner in which the tests are 
used.
     Based on the rapidly evolving nature of genetic tests, 
their anticipated widespread use, and extensive concerns expressed by 
the public about their potential for misuse or misinterpretation, 
additional oversight is warranted for all genetic tests.
    The type of oversight required will differ depending on the stage 
of development of the test and whether it falls into the ``high-
scrutiny'' or ``low-scrutiny'' categories. However, several actions 
could be taken to strengthen the federal oversight role to ensure that 
some level of review occurs for all tests. In particular, the roles of 
CLIA and FDA in oversight should be strengthened and expanded.
     The Food and Drug Administration (FDA) should be the lead 
federal agency responsible for reviewing, approving, and labeling of 
all new genetic tests. FDA review should focus on the claims of 
analytical and clinical validity made by the developer of the test and 
be appropriate to the level of scrutiny warranted by the test. The 
agency should develop flexible mechanisms for review of new genetic 
tests that minimize both the time and the cost of review without 
jeopardizing the quality of the assessment of test validity. These 
mechanisms should, for example, include the use of deemed reviewers and 
standards developed in concert with professional organizations.
    Various elements of a genetic test (analytical validity, clinical 
validity, clinical utility, and test methodology) raise different 
issues that require further oversight. A genetic test should not be 
used in clinical practice (that is, for other than research purposes) 
unless it has been shown to detect reliably the mutation that it is 
intended to detect. CLIA 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 evaluated during a CLIA inspection. SACGT believes 
that the current system requires review. Standards should be enhanced 
to assist laboratories in deciding when a test's analytical validity 
has been determined and is acceptable, or laboratories should be 
required to obtain the concurrence of an independent third party before 
a test is offered for use in clinical practice.
     Clinical Laboratory Improvement Amendment regulations 
should be augmented to provide more specific provisions for ensuring 
the quality of laboratories conducting genetic tests.
    The additional oversight and data collection efforts recommended by 
SACGT will require enhanced resources.
     DHHS agencies should be provided with sufficient resources 
to carry out expanded oversight of genetic tests, including coordinated 
data collection, review, and information dissemination.
    Finally, professional organizations and state health departments 
can provide additional oversight protections. Organizations such as 
CAP, ACMG, and NCCLS have developed guidelines and standards for the 
development and use of genetic tests, and they continue to do so; state 
health departments may require laboratory facilities and personnel that 
perform genetic tests be licensed, and importantly, patient advocacy 
groups as well as individuals and families affected with a genetic 
condition will continue to play an important role in setting standards 
and in developing guidelines.
    Issue 5: What is an appropriate level of oversight for each 
category of genetic test?
    At this time, no systematic or credible mechanism is in place for 
reviewing evidence about genetic tests before they are introduced into 
clinical practice using standardized methodologies. Thus, it is 
difficult to determine with great certainty when a test is ready to 
move from research to clinical practice. (In clinical practice, test 
results go back to the patient or the patient's family, as opposed to 
only being part of data collection.) In addition, once tests enter the 
health care system, it is difficult to retrieve data on their use and 
outcomes. SACGT concluded that although genetic tests should be 
evaluated at all stages, from development through clinical application, 
the level and focus of review should be appropriate to the stage and 
complexity of the test itself. For example, diagnostic tests for a 
disease with high penetrance and for which an intervention is available 
may require less scrutiny than predictive tests for a disease for which 
no proven intervention is available.
    Also important is the degree to which benefits are provided by 
positive and negative test results. In general, genetic tests should 
provide information that people will find useful in making decisions 
relating to their health and well-being. Some consumers might assume 
that a test would not be made

[[Page 21107]]

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 a 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 additional oversight may be needed to ensure greater 
awareness of the utility of the test.
    In considering the level of oversight 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 unnecessarily 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 implications for 
resources that may affect the costs of genetic tests and public access 
to them.
    The public comments emphasized a need for guidelines or national 
standards to determine when a test is ready for clinical use. Many 
commenters stated that a test should be considered ready for clinical 
use when clinical validity and utility have been demonstrated. One said 
that investigational tests are ready for general use ``only when 
sufficient data has been collected and evaluated to determine accuracy, 
validity, and utility in different populations.'' Participants in the 
public meeting said that it was important that the benefits of 
immediate test application be weighed against what might be lost if the 
test is not available. In general, commenters thought that tests for 
rare diseases should be given special considerations so that their 
availability would not be limited. One said that special consideration 
for genetic tests for rare diseases ``must be given in order to ensure 
access to such tests, even before validity is confirmed.''
    Systematic and ongoing review of genetic tests would provide 
information to health care providers and individuals to assist their 
decision-making about the usefulness of the test and its potential 
risks and benefits. The level of confidence in the information 
presented to individuals on genetic tests should be high.
    Making information available and understandable about a test's 
accuracy and predictive power and the availability of therapy for the 
disease the test is designed to test for is important to the public, 
but most commenters thought that this would not be a sufficient form of 
oversight. Similarly, while commenters believed that the review of 
promotional materials would be an important part of the oversight 
process of genetic tests, this alone would not be sufficient for 
oversight.
    Ongoing review is essential, because when test manufacturing 
methods and materials change, either deliberately or inadvertently, the 
performance characteristics of a test can change as well, altering its 
analytical validity. Although CLIA requires reevaluation of tests when 
the methodology changes, stronger incentives are needed to re-qualify 
tests when methods and materials change to demonstrate equivalent 
analytical validity performance.
    In addition to considering the levels of oversight required, SACGT 
considered the timing of such oversight. Because the clinical validity 
of tests changes as it is used in a population, oversight must consider 
the entire continuum of test introduction and use over time, from the 
earliest stages of research to wide-scale clinical application.
    SACGT determined that different levels of oversight are warranted 
for different phases and types of genetic tests. Specific 
recommendations are made for tests in the research phase of 
development, the review of tests prior to clinical and public health 
use, and tests already on the market.
Oversight of Tests in the Research Phase of Development
    Analytical validity should be determined in the research phase. 
Clinical validity can be established only by the expansion of testing 
to larger numbers of people. Thus, a test in the research phase must 
satisfy somewhat different standards than one that has been widely used 
in clinical settings. There must also be a rationale for a test's 
clinical application and for establishing a population in which testing 
would be appropriate. In some cases, laboratories that are developing 
genetic tests for eventual use in clinical practice conduct studies 
using identifiable patient samples. xiv 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. Further, at 
present, not all facilities developing genetic tests have IRB oversight 
bodies in place, because IRBs are not legally required for institutions 
that do not conduct DHHS-funded research.
     Institutional Review Board review should be conducted of 
all research protocols for genetic tests in which individually 
identifiable human subjects or samples are used, regardless of the 
funding source. Institutions that lack an IRB must obtain the services 
of a qualified board. Efforts will be needed to ensure that IRBs are 
suitably equipped to carry out these reviews. In addition, informed 
consent must be obtained from all subjects participating in such 
research.
Transition of Genetic Tests to Clinical and Public Health Use
    Once a laboratory has established the analytical validity of a 
test, its clinical validity and utility can be established only by 
testing in human populations. Questions must be answered 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 process, often requiring years of work. At the 
same time, many would like to see gene discoveries quickly 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 how laboratories determine 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. 
FDA should play a central role in serving as the ``gatekeeper'' for the 
introduction of new tests and should have the resources to carry out 
timely reviews.
    Many tests are likely to fall into the ``low-scrutiny'' category 
and would receive expedited review. For those tests that raise 
concerns--because they are predictive rather than diagnostic, weakly 
penetrant, detect a disorder for which no proven intervention exists, 
or detect a gene mutation in a subpopulation at greater risk for stigma 
or discrimination--greater scrutiny is warranted.
     FDA should give particular attention to the review of 
genetic tests that are used to predict diseases and conditions for 
which no safe and effective interventions are available. Other tests 
may also warrant a higher

[[Page 21108]]

level of scrutiny in the FDA review process.
     In the future, tests may be developed that raise major 
social and ethical concerns. Because FDA's review will focus on 
assuring the analytical and clinical validity of a test, the agency's 
capacity to assess the ethical and social implications of a test may 
not be sufficient. The Secretary should consider the development of a 
mechanism to ensure the identification, and appropriate review, of 
tests that raise major social and ethical concerns.
    SACGT can play an important coordinating role in the oversight of 
genetic tests. The Committee, which includes nonvoting liaison members 
from AHRQ, CDC, FDA, HCFA, HRSA, and NIH, made a commitment to follow 
the progress of DHHS in implementing enhanced oversight and to provide 
ongoing advice about the oversight issues as necessary. SACGT should 
not engage in case-by-case review of genetic tests, but should serve as 
a forum for public discussion of evolving concerns about the issues 
raised in the approval, release, and ongoing review of genetic tests.
Review of Tests Already on the Market
    SACGT believes that some tests already on the market should be 
further evaluated for clinical efficacy and that guidelines should be 
developed for their appropriate use. A body similar to the U.S. 
Preventive Services Task Force could be constituted to conduct such 
reviews. Such a group could develop methodology that emphasizes 
systematic analytic procedures to review scientific evidence for the 
purpose of developing sound practice guidelines for genetic testing. 
Evaluations could be submitted for consideration by medical 
organizations, specialty societies, government agencies, and other 
groups concerned with the delivery of genetic services and could be 
published in peer-reviewed medical journals and other publications.
     The U.S. Preventive Services Task Force with augmented 
resources, or a similar body set up or given deemed status for this 
purpose, should review genetic tests that are already on the market for 
evaluation of clinical efficacy and development of guidelines about 
their appropriate use.
Additional Recommendations for the Appropriate Use of Genetic Tests
    In addition to responding to the five questions in its charge, 
SACGT developed several recommendations directed toward improving the 
safe and responsible introduction of genetic tests to the public.
     Individual and family members considering a genetic test 
should have access to appropriate genetic education and counseling 
resources to ensure their ability to make an informed decision about 
being tested.
    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 those 
considering genetic testing and their family members.
     Written informed consent should be obtained for tests used 
for predictive purposes. The extent to which written informed consent 
should be obtained for all other genetic tests requires further 
deliberation.
    Even after a test has been accepted into clinical practice, some 
observers have suggested that because of the predictive power of 
genetic tests and the impact that test results may have on individuals 
and their families, tests should not be administered unless the 
individual has been fully informed of the test's risks and benefits and 
a written informed consent has been obtained. There is currently no 
requirement for such an informed consent.
     Current regulations under FDA and the Federal Trade 
Commission should be enforced in the area of genetic test 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 to permit the 
promotion and advertising of genetic tests, while also emphasizing 
taking action against those who make false or deceptive claims.

Conclusion

    On March 15, 2000, SACGT forwarded its preliminary draft 
recommendations to Dr. Satcher. The Committee invites public comment on 
this preliminary draft of its conclusions and recommendations, and at 
its next meeting, June 5-7, 2000, the Committee will review the 
comments received and will develop a final report to the Secretary. 
With the completion of this assignment, SACGT will move on to consider 
a number of other high-priority issues, relevant to genetic tests and 
not addressed in this report.
    \i\ 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
    \ii\ McGovern, M.M.; Benach, M.O.; Wallenstein, S.; et al. 
Quality assurance in molecular genetic testing laboratories. JAMA 
281(9): 835-40, 1999.
    \ iii\ Holtzman, N.A.; Watson, M.S. (eds.) Promoting Safe and 
Effective Genetic Testing in the United States: Final Report of the 
Task Force on Genetic Testing. Baltimore: Johns Hopkins University 
Press, 1997.
    \iv\ The consultation document was mailed to 2,500 individuals 
and organizations in late November 1999, and comments were received 
until January 31, 2000. A public meeting was held at the University 
of Maryland, Baltimore, on January 27, 2000, which was planned and 
organized by a steering group composed of SACGT members and 
additional experts knowledgeable about issues of concern to diverse 
communities.
    \v\ Some of the information presented in this section 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.
    \vi\ Farlow, M.R.; et al. Treatment outcome of tacrine therapy 
depends on apolipoprotein genotype and gender of the subjects with 
Alzheimer's disease. Neurology 50(3): 669-77, 1998.
    \vii\ The term analytical validity refers to how well a test 
performs in the laboratory, that is, how well the 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.) In other words, does the test do what its makers claim 
it does? If so, it must produce the same results repeatedly and in 
different laboratories (given the same set of procedures).
    \viii\ Clinical validity refers to the accuracy with which a 
test predicts the presence or absence of a clinical condition or 
predisposition. Thus, a test would be clinically valid if it 
successfully detects the disease or predisposition. Initially, the 
test has to be conducted on individuals who are known to have the 
condition (as well as those who do not) to determine its success 
rate.
    \ix\ Clinical utility refers to the usefulness of the test and 
the value of the information to the person being tested. If a test 
has utility, it means that the results--positive or negative--
provide information that is of

[[Page 21109]]

value to the person being tested because he or she can use that 
information to seek an effective treatment or preventive strategy. 
Even if no interventions are available to treat or prevent the 
disease or condition, there may be benefits associated with 
knowledge of a result.
    \x\ Prevalence refers to the percentage of a population that is 
affected with a particular disease at any given time.
    \xi\ A genetic test may either have positive predictive value 
(the probability that an individual with a positive test result will 
develop the disease) or negative predictive value (the probability 
that an individual with a negative result will not get the disease), 
depending upon its clinical sensitivity and specificity (clinical 
validity).
    \xii\ National Research Council. Committee for the Study of 
Inborn Errors of Metabolism. Genetic Screening: Programs, 
Principles, and Research. Washington, DC: National Academy of 
Sciences, 1975.
    \xiii\ Penetrance is a concept indicating the likelihood that a 
given gene will result in disease. For example, if a condition is 
not expressed in every person who carries the mutation, it is said 
to have reduced penetrance.
    \xiv\ The National Bioethics Advisory Commission has addressed 
ethical issues concerning the use of human biological materials in 
research and made a number of recommendations relevant to some of 
the issues discussed here. National Bioethics Advisory Commission. 
Research Involving Human Biological Materials: Ethical Issues and 
Policy Guidance. Report and Recommendations of the National 
Bioethics Advisory Commission. 1999.

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).

    Date: April 14, 2000.
Sarah Carr,
Executive Secretary, SACGT.
[FR Doc. 00-9808 Filed 4-18-00; 8:45 am]
BILLING CODE 4140-01-P