Federal Register / Vol. 65, No. 236 / Thursday, December 7, 2000 / Notices 76643

Subject: Amendment of 73.202(b)

Table of Allotments FM Broadcast

Stations (Windthorst, Texas).

Number of Petitions Filed: 2.

Federal Communications Commission.

Magalie Roman Salas,

Secretary.

[FR Doc. 00–31174 Filed 12–6–00; 8:45 am]

BILLING CODE 6712–01–M

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.

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 email 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

p.m.

FOR FURTHER INFORMATION CONTACT:

Questions about this request for public

comment can be directed to Dr. Susanne

Haga, by e-mail (hagas@od.nih.gov) 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

76644 Federal Register / Vol. 65, No. 236 / Thursday, December 7, 2000 / Notices

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, populationbased 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, peerreviewed 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

Federal Register / Vol. 65, No. 236 / Thursday, December 7, 2000 / Notices 76645

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 peerreviewed 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.

BILLING CODE 4140–01–P

76646 Federal Register / Vol. 65, No. 236 / Thursday, December 7, 2000 / Notices

[FR Doc. 00–31218 Filed 12–6–00; 8:45 am]

BILLING CODE 4140–01–C

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Office of the Secretary

Meeting of the National Human

Research Protections Advisory

Committee

AGENCY: Office of Public Health and

Science, Office for Human Research

Protections, HHS.

ACTION: Notice of first meeting.

SUMMARY: Pursuant to section 10(d) of

the Federal Advisory Committee Act, as

amended (5 U.S.C. Appendix 2), notice

is hereby given of a meeting of the

National Human Research Protections

Advisory Committee.

The meeting will be open to the

public, with attendance limited to space

available. Individuals who plan to

attend and need special assistance, such

as sign language interpretation or other

reasonable accommodations, should

notify the contact person listed below.

Individuals planning on attending the

meeting and who want to ask questions

must submit their questions in writing

in advance of the meeting to the contact

person listed below.

DATES: The Committee will hold its next

meeting on December 20–21, 2000. The

meeting will convene from 8:30 a.m. to

its recess at 4:30 p.m. on December 20th

and resume at 9 a.m. to 3 p.m. EST on

December 21st.

ADDRESSES: Bethesda Marriott-Pooks

Hill, 515 Pooks Hill Road, Bethesda,

Maryland 20814, (301) 897–9400.

FOR FURTHER INFORMATION CONTACT: Mr.

Garey Rice, Administrative Officer,

Office for Human Research Protections,

6100 Executive Boulevard, Room 310B

(MSC 7507), Rockville, Maryland

20892–7507, (301) 402–6003. The

electronic mail address is:

gr66s@nih.gov.

SUPPLEMENTARY INFORMATION: The

National Human Research Protections

Advisory Committee was established on

June 6, 2000 to provide expert advice

and recommendations to the Secretary

of HHS, Assistant Secretary for Health,

the Director, Office for Human Research

Protections, and other departmental

officials on a broad range of issues and

topics pertaining to or associated with

the protection of human research

subjects.