21094 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

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.

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 hagas@od.nih.gov. 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

(hagas@od.nih.gov) 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

Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices 21095

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 postmarketing 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

21096 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

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 NIHDOE 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 diseaseassociated 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

Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices 21097

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 broadbased 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

21098 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

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 antidiscrimination 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

Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices 21099

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 postanalytical 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

21100 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

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 (analytespecific 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 highcomplexity 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 DNAbased 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 DHHSfunded 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, populationbased, 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 patientphysician 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

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

21102 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

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

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

21104 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

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, firstdegree 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 selfperception 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?

Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices 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 Internetbased 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 postmarketing data on genetic tests available

21106 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

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 postanalytical 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 ‘‘lowscrutiny’’ 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

Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices 21107

available unless it has a health benefit.

For example, a negative genetic test

result may provide a useful basis of

information for informed decisionmaking. 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 requalify 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 DHHSfunded 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

21108 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

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. iThese 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 iiMcGovern, M.M.; Benach, M.O.;

Wallenstein, S.; et al. Quality assurance in

molecular genetic testing laboratories. JAMA

281(9): 835–40, 1999. iiiHoltzman, 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. ivThe 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. vSome 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. viFarlow, 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. viiThe 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). viiiClinical 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. ixClinical 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

Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices 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. xPrevalence refers to the percentage of a

population that is affected with a particular

disease at any given time. xiA 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).

xiiNational Research Council. Committee

for the Study of Inborn Errors of Metabolism.

Genetic Screening: Programs, Principles, and

Research. Washington, DC: National

Academy of Sciences, 1975. xiiiPenetrance 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. xivThe 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),

sc112c@nih.gov (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]

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