[Federal Register Volume 65, Number 236 (Thursday, December 7, 2000)]
[Notices]
[Pages 76643-76646]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-31218]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


Secretary's Advisory Committee on Genetic Testing

AGENCY: Office of the Secretary, DHHS.

ACTION: Request for public comment on a proposed classification 
methodology for determining level of review for genetic tests.

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SUMMARY: The Secretary's Advisory Committee on Genetic Testing (SACGT) 
was chartered to advise the Department of Health and Human Services on 
the medical, scientific, ethical, legal, and social issues raised by 
the development and use of genetic tests. SACGT recently completed its 
first report, Enhancing the Oversight of Genetic Tests (available at 
http://www4.od.nih.gov/oba/sacgt.html). One of SACGT's major 
recommendations was that all new genetic tests be reviewed by the Food 
and Drug Administration (FDA) before they are used for clinical care or 
public health purposes through ``new and innovative oversight 
mechanisms that will not limit the development of new tests or 
inordinately delay their availability.'' SACGT also recommended that 
FDA correlate the level of review applied to each genetic test with the 
level of scrutiny warranted by the test.
    To assist FDA in determining which tests warrant greater scrutiny, 
SACGT is developing a classification methodology. A SACGT Working Group 
on Genetic Test Classification, composed of SACGT members and ad hoc 
experts, met on August 3, 2000, to identify criteria for assessing the 
risks and benefits of genetic tests that could serve as the basis for a 
classification scheme. The full Committee endorsed the working group's 
approach on August 4, 2000. Due to further analysis of the proposed 
approach and concerns raised by professional genetics and laboratory 
organizations about its practicality, SACGT revisited the initial 
proposal at its November 2-3 meeting. SACGT modified the methodology 
and agreed that additional input from public and professional 
organizations should be gathered. It is now seeking public comments on 
the rationale and feasibility of the proposed test classification 
methodology and several specific questions.

DATES: The public is encouraged to submit written comments on the 
proposed classification methodology by January 25, 2001 in order for 
SACGT to consider the comments at its next meeting in February 2001. 
The following mailing address should be used: SACGT, National 
Institutes of Health, 9000 Rockville Pike, Building 1, Room 103, 
Bethesda, Maryland, 20892. SACGT's facsimile number is 301-496-9839. 
Comments can also be sent via e-mail to [email protected]. All public 
comments received will be available for public inspection at the SACGT 
office between the hours of 8:30 a.m. and 5 p.m.

FOR FURTHER INFORMATION CONTACT: Questions about this request for 
public comment can be directed to Dr. Susanne Haga, by e-mail 
([email protected]) or telephone (301-496-9838). The methodology will 
also be posted on SACGT's website for review and comment.

SUPPLEMENTARY INFORMATION:

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. According 
to GeneTests, a genetic testing laboratory directory, genetic testing 
is clinically available for more than 400 diseases or conditions in 
more than 200 laboratories in the United States, and investigators are 
exploring the development of tests for an additional 338 diseases or 
conditions. However, most of the current genetic testing is for single 
gene disorders such as Huntington disease and cystic fibrosis.
    Genetic tests can be performed for a number of purposes. Moreover, 
a test can be used in more than one way, such as when a test used for 
diagnostic purposes is also used to predict risk of disease. SACGT 
included the following types of testing within its definition: (1) an 
analysis performed on human DNA, RNA, genes, and/or chromosomes to 
detect heritable or acquired genotypes, mutations, phenotypes, or 
karyotypes that cause or are likely to cause a specific disease or 
condition; and (2) the analysis of human proteins and certain 
metabolites, which are predominantly used to detect heritable or 
acquired genotypes, mutations, or phenotypes. The purposes of both 
these types of genetic tests include predicting risks of disease, 
screening of newborns, directing clinical management, identifying 
carriers, and establishing prenatal or clinical diagnoses or prognoses 
in individuals, families, or populations. Not included in this 
definition are tests that are used primarily for other purposes, but 
that may contribute to diagnosing a genetic disease (e.g., blood smear, 
certain serum chemistries), and tests conducted exclusively for 
forensic identification purposes.
    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, and in general, such tests are not recommended for 
individuals without such a history. However, in the future, the use of 
predictive tests may expand and be offered to individuals without a 
family history of certain diseases and conditions, e.g., common adult-
onset disorders.
    In Enhancing the Oversight of Genetic Tests, SACGT recommended that 
all new genetic tests be reviewed by the Food and Drug Administration 
(FDA) before they are used for clinical care or public health purposes. 
The Committee suggested that FDA's review be accomplished through ``new 
and innovative oversight mechanisms that will not limit the development 
of new tests or inordinately delay their availability.'' Determining 
the level of review required of a particular genetic test is crucial to 
ensuring that a test receives the appropriate level of review based on 
the characteristics of the test and its target disease or condition. In 
order to determine the appropriate level of review for genetic tests, 
SACGT concluded that a classification methodology was needed.
    To assist FDA in determining the appropriate level of review, a 
working group on genetic test classification was convened in August, 
composed of SACGT members and ad hoc experts. The goal of the working 
group was to

[[Page 76644]]

develop criteria for assessing the risks and benefits of genetic tests 
that would serve as the basis for a classification scheme. In 
classifying genetic tests by the level of review warranted, the working 
group explored a number of factors that could be used, including test 
characteristics (analytical validity, clinical validity, and clinical 
utility), availability of safe and effective treatments, and the social 
consequences of a diagnosis or identification of risk status. They also 
considered whether the test would be for a common or an orphan (rare) 
disease or mutation; whether the test will be used for population-based 
screening or testing of individuals; whether the test is used to detect 
germline or somatic mutations; whether the test is primarily used for 
predictive or diagnostic purposes; the complexity of the test; the 
level of difficulty in interpreting test results; whether the mutation 
being tested for is highly or weakly penetrant (the likelihood of 
developing a disease or condition); and the availability of independent 
methods of confirmation to reduce the occurrence of false-positive test 
results.

Proposed Test Classification Methodology for Determining Level of 
Review for Genetic Tests

    In SACGT's August draft of the classification methodology, the 
working group developed two levels of review and four criteria to be 
used in the determination of review level for genetic tests. The four 
criteria related to test volume; whether a test is to be used for 
population-based screening; the purpose of the test (predictive or 
diagnostic); and for predictive tests, the availability of an 
intervention, the predictive value of the testing process, or 
significant medical or social risks associated with the test. After 
further deliberation and discussion of the proposed test classification 
methodology, SACGT modified the methodology at its November meeting. 
The modified approach maintains the two levels of review initially 
proposed (Level I and Level II) but revises and reduces the number of 
criteria. The revised criteria relate to analytical validity, 
population-based screening, and frequency of disease. SACGT is seeking 
public comment on this revised test classification methodology.

Classification Structure and Levels of Review

    SACGT determined that two levels of review would provide the most 
straightforward review process for all new genetic tests. In SACGT's 
proposed classification methodology, tests for rare diseases or 
conditions, with the exception of those used for population screening, 
would receive a Level I review and all other new genetic tests would 
receive a Level II review. While details of the review processes have 
yet to be fully defined, the Committee has outlined its expectations 
for each review level.
    A Level I review would be a streamlined review process that would 
involve assurances of pre-test/post-test information according to a 
standard template and, possibly, data collection from existing 
resources. SACGT currently proposes that pre-test information include a 
description of the purpose of the test, the clinical condition for 
which the test is performed, the definition of the test (specific 
laboratory protocol), and evidence of analytical and clinical validity. 
Less evidence of data would be permitted in Level I. The Level II 
review process would include a detailed review of pre-test/post-test 
information and, possibly, new data collection initiatives.
    SACGT suggests that both review levels consider the use of 
standards developed in consultation with professional organizations, 
consumer representatives, and other relevant groups; post-market 
adverse event reporting; and assurances for informed consent as 
appropriate. SACGT also suggests that, as appropriate, peer-reviewed 
literature could be used to substantiate claims of analytical and 
clinical validity.

Classification Criteria

    The three criteria SACGT proposes to use in determining the level 
of review of a genetic test are analytical validity, population 
screening, and frequency of disease. The first criterion is an 
essential feature that all genetic tests should be able to demonstrate. 
The two other criteria classify genetic tests according to the number 
of people who may be affected by the disease or condition.
    SACGT believes that all tests should be analytically valid and that 
no test should be considered for further review unless shown to be so. 
Analytical validity is defined as the ability of a test to measure or 
detect the analyte it is intended to measure or detect. An analyte is 
defined as the substance measured by a laboratory test, e.g., DNA--
mutation, allele, or chromosome, metabolites, or enzyme activity. 
Analytical validity includes analytical sensitivity (the probability 
that a test will detect an analyte when it is present in the sample) 
and analytical specificity (the probability that a test will be 
negative when an analyte is absent from a sample).
    Population screening is the second criterion in the classification 
methodology. Population screening affects large numbers of people, most 
of whom are currently healthy. The risks of false-positive and false-
negative test results need to be carefully evaluated. The type of 
follow-up for individuals who test positive must be clear and proven. 
In this schema, the definition of a population-based test is a test 
intended for use on a cluster of individuals who are identified as a 
group or population (>1000) on the basis of shared ethnicity, class, 
geographical location, gender, age, or other characteristics such as 
pregnancy, behavior (e.g., smoking), physical traits (e.g., baldness or 
height), or occupation in which the frequency of the disease allele or 
predispositional risk to be determined is higher than the frequency or 
risk in the general population. Carrier screening for Tay-Sachs disease 
in the Ashkenazi Jewish population would be considered a population-
based test. Another example would be a test used for all newborns.
    The third criterion SACGT proposes to include in the classification 
methodology is the frequency of the disease. This criterion would 
divide tests according to whether they test for a common disease or 
rare disease. SACGT proposes to define a rare disease or condition as 
having a prevalence of less than one in 2,000 individuals or an 
incidence less than one in 10,000 individuals.
    There were a number of reasons why SACGT chose to divide genetic 
tests on the basis of whether it was for a rare disease versus a common 
disease. The Committee believes that tests for common diseases or 
conditions should receive a higher level of review for two reasons. 
First, the molecular and metabolic basis of common diseases is often 
complex. Recent findings have shown that the genetic etiology of common 
diseases and conditions is not as straightforward as traditional 
Mendelian disorders and likely involve the consideration of a number of 
other factors such as environment, lifestyle, and other genetic 
factors. For this reason, a higher level of review and larger clinical 
studies may be necessary to demonstrate the accuracy and validity of 
tests for common diseases or conditions. Second, tests for common 
diseases or conditions have the potential to affect a greater number of 
people.
    The Committee wishes to make recommendations that will facilitate 
the continued development and availability

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of tests for rare diseases and conditions. SACGT would not want to see 
the cost of, and time required for, review to become barriers to the 
provision of genetic tests for rare diseases, particularly those 
provided in the academic setting, given the limited financial resources 
and income of these laboratories.

Applying the Classification Methodology

    These three criteria would be considered in a step-wise manner 
leading to a determination of the appropriate level of review warranted 
by a particular genetic test (see figure). When determining the level 
of review for a particular test, SACGT proposes that a test's 
analytical validity be ascertained first. If a test was shown to be not 
analytically valid, it would be automatically rejected. If a test was 
shown to be analytically valid, it would move on to the next criterion 
of population screening. In the Committee's view, tests used for 
population screening should receive a higher level of review because of 
the large number of people it would affect. If a test is to be used for 
population screening, it would receive a Level II review. If a test is 
not to be used for population screening, the third criterion would be 
applied. If the test is used to detect a rare disease or condition, it 
would receive a Level I review. Since it may take many years to gather 
large numbers of affected individuals for study, a Level I review would 
permit smaller data sets. Documentation would need to be provided to 
support the claim that a test is for a rare disease or condition. 
References may include peer-reviewed literature citations, specialized 
medical society proceedings, or governmental statistical publications. 
When no such studies or literature citations are available, the 
applicant may be able to demonstrate prevalence or incidence by 
providing credible conclusions from appropriate research or surveys. A 
rare disease test may sometimes warrant a Level II review. All other 
tests would receive a Level II review.

Questions on Which Comment Is Being Solicited

    In order to ensure that a comprehensive and appropriate 
classification methodology is developed, SACGT would appreciate 
receiving public comment on the rationale and feasibility of the 
proposed test classification methodology. In addition, SACGT is 
interested in receiving input on the following specific questions:
    1. Is the number of review levels appropriate? Should there be more 
than two levels? Should all genetic tests receive the same level of 
review?
    2. Are the criteria of analytic validity, population screening, and 
frequency of disease appropriate for determining the proper review 
level? Should other criteria, such as the intended use of a genetic 
test (e.g., diagnostic, predictive, carrier, prenatal, etc.) or 
clinical utility, be considered in the classification of tests? If so, 
how should they be incorporated into the methodology?
    3. Are the proposed definitions for population and rare diseases 
appropriate?
    4. SACGT has not proposed a specific threshold or minimum standard 
for analytical validity. Should a threshold for analytical validity be 
defined? If so, what should the standard be?
    5. What characteristics of a rare disease test would raise the 
level of review from Level I to Level II?

    Dated: November 29, 2000.
Sarah Carr,
Executive Secretary, SACGT.
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[FR Doc. 00-31218 Filed 12-6-00; 8:45 am]
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