Proposed Recommendations of the Task Force on Genetic Testing; Notice of Meeting and Request for Comment

DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

Proposed Recommendations of the Task Force on Genetic Testing;

Notice of Meeting and Request for Comment

AGENCY: National Institutes of Health, HHS.

ACTION: Notice.

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SUMMARY: The Task Force on Genetic Testing was created by the National

Institutes of Health (NIH)-Department of Energy (DOE) Working Group on

Ethical, Legal, and Social Implications of Human Genome Research to

make recommendations to ensure the development of safe and effective

genetic tests, their delivery in laboratories of assured quality, and

their appropriate use by health care providers and consumers. The Task

Force reviewed genetic testing in the United States, promulgated

interim principles consonant with its goals (``Interim Principles'',

available at http://ww2.med.jhu.edu/tfgtelsi), and has taken public

comments into consideration in revising them. Over the past eight

months the Task Force has discussed policies to implement several of

its principles. It now submits proposed recommendations for public

comment. These proposed recommendations are available at http://

ww2.med.jhu.edu/tfgtelsi.

DATES: To assure consideration by the Task Force, comments must be

received on or before March 10. The Task Force will meet on March 17

from 8:00 a.m. to recess and on March 18 from 8:00 a.m. to adjournment

at approximately 12:00 noon. The meeting will take place at the

Doubletree Inn at the Colonnade, 4 West University Parkway, Baltimore,

Maryland, (410) 235-5400. Time permitting, guests will have the

opportunity to speak on comments already submitted, but no formal time

is being set aside. A final report, including the principles and

recommendations, together with background information and comments,

will be issued shortly after the meeting.

ADDRESSES: Written comments should be sent to Neil A. Holtzman,

M.D.,M.P.H., Genetics and Public Policy Studies, The Johns Hopkins

Medical Institutions, 550 N. Broadway, Suite 511, Baltimore MD, 21205-

2004, faxed to Dr. Holtzman at 410-955-0241, or e-mailed to tfgt-

[email protected]. Individuals who plan to attend the March 17-

18 meeting and need special assistance, such as sign language

interpretation or other reasonable accommodations, should contact Dr.

Holtzman in advance of the meeting.

Background

Scientific breakthroughs have greatly accelerated the discovery of

genes which, when altered by mutation, result in disease or in

increased risk of disease. When these mutations occur in the germline

(sperm or egg), they can be passed from one generation to the next.

These basic research discoveries lead readily to the development of

tests for inherited mutations. The number of DNA-based genetic tests

and the volume of testing are increasing steadily. This has been

accomplished in part by the work of the new biotechnology industry.

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Aware of the potential for harm as well as benefits, the National

Center for Human Genome Research (NCHGR/NIH) set aside from its

inception a portion of its appropriation for consideration of ethical,

legal, and social implications of human genome research. As part of its

joint program with NCHGR, the Department of Energy (DOE) also set aside

a portion of its appropriation. This initiative to anticipate problems

in order to maximize benefits and prevent or minimize harm, of which

the Task Force on Genetic Testing is one activity, is unprecedented in

the development and application of new biomedical technologies. The

principles and recommendations of the Task Force represent an attempt

to build on successes and prevent problems of the past and present from

continuing in the future. Some past and present problems will be

described in the final report of the Task Force.

For the most part, genetic testing in the United States has

developed successfully, providing more options for avoiding,

preventing, and treating inherited disorders. This success is largely

the result of testing being undertaken in genetic centers or in

consultation with geneticists and genetic counselors. In the next few

years, the use of genetic testing is likely to expand rapidly while the

number of genetic specialists will remain essentially unchanged. This

means that a greater burden for making genetic testing decisions will

fall on providers who have had little formal training or experience in

genetics. The problems they will encounter in providing genetic tests

are seldom encountered in other areas of medicine.

Much of medical practice and medical testing is provided

for people who are already ill. Genetic testing will increasingly be

used to predict risks of future disease in healthy people. Telling

healthy people about future risks can heighten uncertainty and cause

psychological distress.

For many other disorders, interventions are available to

cure, prevent or ameliorate the condition. This is not the situation

for many disorders for which genetic testing is possible. Positive

results of some tests confront patients with difficult reproductive

decisions. These are personal decisions that should not be unduly

influenced by providers or society.

Few other tests provide information on the risk of future

disease to healthy relatives of the person being tested. Providers have

little guidance in communicating genetic risks to relatives and,

simultaneously, keeping results confidential.

Differences in the frequency of disease-related mutations

among ethnic groups can influence the appropriateness of providing some

genetic tests, and heighten concern about discrimination and

stigmatization.

In addition, the predictions made by genetic tests are not always

certain and often no independent test is available to confirm the

prediction. Test uncertainty is not unique to genetic tests. However,

the psychological and physical effects of testing are often greater for

imperfect genetic tests when no treatment is available or when

interventions of unproven efficacy are life-long or irreversible.

Key Principles

The Task Force enumerated principles to address many of the

problems raised by predictive genetic tests. Its proposed

recommendations are an effort to implement several of these principles,

highlighted below:

Validity and Utility of Genetic Tests

Before a genetic test can be generally accepted in

clinical practice, data must be collected to demonstrate the benefits

and risks that accrue from both positive and negative results. The

primary responsibility for data collection falls on test developers.

For many tests, however, data collection must continue after tests are

introduced into practice.

Protocols for the clinical validation of genetic tests

must receive the approval of an institutional review board (IRB). At

present, IRBs have the principal responsibility for the protection of

subjects participating in validation studies. The Task Force is

concerned that current limitations of IRBs might impair review of

genetic testing protocols.

Laboratory Quality and Certification

A national accreditation program for laboratories

performing genetic tests, which includes on-site inspection and

proficiency testing, is needed to promote standardization across the

country. Although most laboratories providing clinical laboratory tests

are certified under the Clinical Laboratory Improvement Amendments

(CLIA) of 1988, current regulations do not adequately ensure the

quality of genetic testing. Professional organizations have developed

more appropriate quality assessment of genetic tests than is required

under CLIA, but laboratories performing genetic tests are not required

to use these voluntary accreditation mechanisms.

Professional Competence in Genetics

Health care professionals involved in the provision of

genetic tests should be well-informed about their implications,

benefits and risks. Students preparing for careers in health care and

current health care providers themselves are not being taught enough

about human genetics and genetic testing. Consequently, not all

providers in practice today may have adequate competence to offer and

interpret genetic tests. Related problems are the lack of standards for

formal assessment of new genetic testing technologies and the limited

impact of current efforts to establish clinical guidelines for when and

how genetic tests should be offered.

Rare Genetic Diseases

The development and maintenance of tests for rare genetic

diseases must be encouraged. At a time when genetic tests for common

complex disorders are increasing, tests for rare disorders may be

developed at a slower rate than in the past. Some that have been

available may be more difficult or impossible to obtain. Many

physicians do not have access to the best available information and

resources to identify and manage rare diseases, or know where to turn

for help.

Informed Consent and Confidentiality

Informed consent for a validation study must be obtained

whenever the specimen can be linked to the subject from whom it came.

When specimen identifiers are retained in either coded or uncoded form,

the opportunity exists of being able to contact subjects even if the

intent of the original protocol is not to do so.

Health care providers must describe the features of the

genetic test, including potential consequences, to potential test

recipients prior to the initiation of predictive testing in clinical

practice. Individuals considering genetic testing should be told the

purposes of the test, the chance it will give a correct prediction, the

implications of test results and the options, and the benefits and

risks of the process. The responsibility for providing information to

the individual lies with the referring provider, not with the

laboratory performing the test.

It is unacceptable to coerce or intimidate individuals or

families regarding their decision about genetic testing. Respect for

personal autonomy is paramount. People being offered testing must

understand that testing is voluntary. Whatever decision they make,

their care should not be jeopardized. Information on risks and

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benefits must be presented fully and objectively. A non-directive

approach is of the utmost importance when reproductive decisions are a

consequence of testing or when the safety and effectiveness of

interventions following a positive test result have not been

established. Obtaining written informed consent helps to assure that

the person agrees to testing voluntarily.

Results should be released only to those individuals to

whom the test recipient has consented or subsequently requested in

writing. Means of transmitting information should be chosen to minimize

the likelihood that results will become available to unauthorized

persons or organizations. Under no circumstances should results be

provided to any outside parties, including employers, insurers,

government agencies, without the test recipient's written consent.

Unless potential test recipients can be assured that the results will

not fall into unauthorized hands, some will refuse testing for fear of

losing insurance or employment.

Health care providers have an obligation to the person

being tested not to inform other family members without the permission

of the person tested except in extreme circumstances. Disclosure by

providers to other family members is appropriate only when the person

tested refuses to communicate information despite reasonable attempts

to persuade him or her to do so, and when failure to give that

information has a high probability of resulting in irreversible or

fatal harm to the relative. When test results have serious implications

for relatives, it is incumbent on providers to explain to people who

are tested why they should communicate the information to their

relatives.

Recommendations

A Genetics Advisory Committee

The Task Force joins the NIH-DOE Joint Committee to Evaluate

Ethical, Legal, and Social Implications Program of the Human Genome

Project in recommending that the Secretary of Health and Human Services

(HHS) create, in the Office of the Secretary, a federally chartered

Advisory Committee on Genetics and Public Policy (hereafter the

Advisory Committee) whose members should include the stakeholders in

genetic testing. The Secretary should establish formal liaison between

the Advisory Committee and an already-established HHS interagency group

considering policies of the Department relevant to the development and

provision of genetic tests. In addition to assisting the Advisory

Committee, this interagency group should develop coordinated and

consistent genetic testing policies in the Department. The two

committees whose creation is recommended later in this document, one to

advise the Food and Drug Administration (FDA) on assuring the validity

and utility of new genetic tests, the other to advise the Clinical

Laboratory Improvement Advisory Committee on assuring the quality of

laboratories performing genetic tests, should report to the Advisory

Committee through the interagency group.

Need for Interim Action

The Task Force recognizes that the formation of the Advisory

Committee could take some time. It is also aware that organizations

have on occasion developed and offered genetic tests without always

collecting data on test validity and utility and without external

review. Consequently, the public is not being adequately protected.

The Task Force recommends that the Secretary of HHS use existing

agencies and policies to ensure that the public will have adequate

protection from predictive genetic tests that have not been adequately

validated and whose clinical utility has not been established. It

suggests two possibilities:

(1) FDA uses its acknowledged authority under the Medical Device

Amendments of 1976 (21 USC 321-392) to the Food, Drug, and Cosmetic

Act (21 USC 301-392), to ensure that all organizations developing

new, predictive genetic tests submit protocols to an institutional

review board (IRB).

(2) The Health Care Financing Administration (HCFA) establish

policies under Medicare and Medicaid to reimburse for certain

genetic tests (see below) only when they are performed in

laboratories that can provide evidence that (a) the test has been

clinically validated (based on published information or information

provided by the test developer) or that it is participating in a

systematic validation plan, and (b) they are qualified to provide

such tests (see below, Laboratory Quality). Once HCFA adopts such

policies it is likely that other third-party payers will quickly

follow.

The Task Force makes a similar recommendation to the Department of

Defense for reimbursement under the Civilian Health and Medical Program

Uniform Services (CHAMPUS).

The need for stringent scrutiny of certain predictive genetic

tests. The Task Force has sought to find ways to identify tests that

are more likely to pose significant risks in their developmental stage

and when they enter clinical practice. It recognizes that existing

resources for scrutinizing tests are limited. Consequently, the Task

Force has attempted to identify characteristics of tests and diseases

that raise the greatest concern and can be used to prioritize tests for

stringent scrutiny. These characteristics include, but are not

necessarily limited to:

A test's potential for predicting serious future disease

in healthy people (or their offspring). Even if a test developer's

intended use of the test may not be for predictive purposes, the

potential for such use, as is the case for DNA-based genetic tests,

increases the level of scrutiny needed. The absence of a confirmatory

test heightens the scrutiny a test needs.

Test uncertainty. When only healthy people with positive

test results will develop the disease and when all people with positive

results will develop it, less scrutiny is needed than when these

conditions are not fulfilled.

The safety and effectiveness of clinical interventions in

those with positive test results of predictive tests. Unless the safety

and effectiveness of clinical interventions for those with positive

test results have been established, people who test positive cannot be

confident that interventions will prevent the disease or improve its

outcome if it does occur.

Other characteristics that might play a role in prioritizing are:

the frequency of occurrence of the disorder(s) detected by the test

under review, the use of the test for population screening, whether the

disorder(s) detected occur more frequently in some ethnic groups than

others, and whether the reliability of the test under routine clinical

laboratory conditions has been established.

There are several junctures at which these characteristics should

be applied to specific tests. The first occurs in the review of

protocols for investigating the validity and utility of new tests.

Subjects participating in trials or pilot programs to establish

validity and utility must be adequately protected, particularly when

they will be notified of the results or simply when personal

identifiers will be retained with the specimens. The protocol must have

sufficient scientific merit to justify the participation of subjects.

The characteristics provided above could be used by IRBs as a checklist

to make sure that the protocol addresses important issues in test

development. For instance, if applicants fail to present data on test

uncertainty, they should be required to supply that information or, if

it is unavailable, to collect the requisite data. A grading system

could be devised so that protocols exceeding a certain score would be

designated as requiring ``stringent scrutiny.'' Alternatively, the

characteristics can be layered in an

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algorithm or decision tree. (See Figure) For instance, if a test has

the potential to predict future disease and there is no confirmatory

test, the next step in deciding whether it needed stringent scrutiny

would be the extent of test uncertainty. If this was unknown, data

collection would be needed. Once data were collected, the next question

is the safety and effectiveness of interventions in those with positive

results. If the benefit:risk ratio of intervention is high and test

uncertainty is low, the test would not require close scrutiny. Even if

test uncertainty is low, close scrutiny would be needed if the safety

and effectiveness of interventions had not been established.

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The second juncture occurs when a test developer believes the test

is appropriate for clinical use. Review by an organization independent

of the developer is needed to ensure that the public will benefit from

the test. The Task Force is concerned that the number of tests might

overwhelm external review processes and needlessly delay the

availability of tests of potential benefit. To reduce the likelihood of

backlogs, the criteria should be used to set priorities for stringent

scrutiny. Tests of low priority would enter clinical practice without

scrutiny but could be considered again at the third juncture.

The third juncture occurs when the test is clinically available and

there are concerns that (1) it will not be used when it is indicated,

(2) it will be used for inappropriate indication(s), or (3) that more

data on validity and utility are needed. The same set of criteria can

be used to set priorities for post-marketing surveillance requirements

and establishing guidelines for test use.

The Task Force recognizes that as information and experience is

gained, the scrutiny a test needs is likely to diminish. As further

scientific and technical advances occur, other criteria may become more

important and other types of tests may then need stringent scrutiny.

Assuring the Validity and Utility of New Genetic Tests

The Task Force is concerned that the high workload of IRBs, their

variability in community representation, in evaluating protocols, and

in expertise germane to the review of genetic tests, as well as the

conflicts of interest that can arise in local review, impairs current

review of genetic tests that warrant stringent scrutiny. The Task Force

urges the Office of Protection of Human Subjects from Research Risks,

with input from the proposed Advisory Committee, to address these

problems. The Task Force is also concerned that organizations that do

not use federal funds for the research and development of genetic tests

that will be marketed as services may not seek outside review from an

independent IRB. The Task Force is also concerned that data needed

after tests enter clinical practice may not be collected.

The Task Force urges the proposed Advisory Committee to recommend

to the Secretary the creation of a National Genetics Board (NGB) whose

goal would be to assure the protection of human subjects in the

development of genetic tests with the potential to predict future

disease. NGB members should be broadly representative of stakeholders

in genetic testing, including but not limited to test developers

(manufacturers and clinical laboratories), consumers, professional

societies, health care providers, and insurers. Some of its members

must be scientists capable of reviewing scientific protocols. The Board

should have its own staff.

NGB would develop a checklist that would enable local IRBs to

identify protocols that meet criteria for stringent scrutiny. NGB would

function along the lines of one of the following models, each of which

each has advantages and disadvantages. The Task Force did not reach

consensus on which model NGB should follow. The Task Force is

especially interested in public comments on the alternatives.

(1) NGB reviews all protocols requiring stringent scrutiny. This

assures that expert assessment with broad input will be consistently

obtained and conflicts of interest will be minimized. However, if local

IRBs also review protocols before or after they are sent to the NGB,

funding or activation of the protocols could be delayed. NGB approval

would be required before federal funds are awarded. NGB should also be

available to review protocols from commercial organizations developing

genetic tests without federal funds.

(2) NGB has the discretion to choose which protocols among those in

need of stringent scrutiny it will review. Those protocols which NGB

elects not to review will be sent back to the local IRB for review.

Based on its selective review, NGB will issue advisories to local IRBs

to assist them in the review of similar protocols. Under this model,

the advantages of the first model are reduced, but so is NGB's work

load; local IRBs retain greater authority. Delays are likely as

protocols move between local IRBs and NGB.

Under both model (1) and (2), local IRBs could also request NGB

review of other genetic testing protocols. Based on its available

resources and backlog, NGB could decide whether or not to review these

protocols. NGB could also assume responsibility for the primary review

for the protection of human subjects of multi-center and other

collaborative studies for the validation of genetic tests.

(3) NGB focuses on generic policy issues and sets general

guidelines for review. It is available for consultation and advice, but

has no mandatory review function. Protocols that a local IRB believes

raises novel and problematic issues could be sent to NGB for analysis

and comment. The advantages and disadvantages of this approach are

similar to those described for the second model; the likelihood of

consistent review is further reduced, but as review is entirely the

responsibility of the local IRBs, delays are less likely.

Role of FDA. The Task Force recognizes that developers of genetic

tests who do not rely on federal funds are under no legal obligation to

submit protocols to the proposed NGB and have not always obtained IRB

approval for validation protocols of tests they plan to market as

laboratory services. If tests requiring stringent scrutiny were

regulated by FDA, even if they were to be marketed as services, then

under existing regulations (21 CFR part 56), protocols for clinical

validation would have to be submitted to an IRB regardless of whether

they came from federally-funded organizations or not. Although the FDA

acknowledges its authority under the Medical Device Amendments to

regulate genetic tests marketed as services, it has chosen not to do

so. (Under the CLIA, clinical laboratories must demonstrate analytical

validity of their tests but there is no statutory or regulatory

requirement for them to establish the clinical validity or utility of

clinical laboratory tests.)

The Task Force recommends that FDA:

(1) Establish a Genetics Advisory Panel under the Medical Devices

Amendments (21 USC 321-392) which would advise FDA on: (a) Strategies

for prioritizing genetic tests; (b) the scientific, ethical, and social

merits of applications FDA receives for marketing genetic tests; and

(c) other matters germane to genetic testing. In carrying out its first

function, this panel could consult with the proposed NGB if it is

established, but it should not delay formulating its strategies until

that time.

(2) Adopt a strategy to prioritize predictive genetic tests

according to the degree of scrutiny they need.

(3) Publicize the requirements it develops for tests requiring

stringent scrutiny.

(4) Require that new genetic tests meeting criteria for stringent

scrutiny be regulated under the Medical Device Amendments (21 USC 321-

392; 21 CFR parts 200 et seq.) regardless of whether their sponsor's

intention is to market them as services or as kits.

Although a majority of the Task Force supported all of these

recommendations, a consensus was not reached on the fourth. The Task

Force is especially interested in public comments on this

recommendation.

Data collection. The data needed to definitively establish the

validity and utility of a genetic test may take so long to collect that

if test developers could

[[Page 4545]]

not market their tests they would be deterred from developing them.

Data collection is also a problem for rare genetic diseases for which

data from several sources will have to be collected to establish the

validity and utility of testing. Without a formal plan and procedure

for prospective data collection, data will undoubtedly be lost and the

time to reach definitive conclusions will be prolonged.

The Centers for Disease Control and Prevention (CDC), in

cooperation with NCHGR, should expand the monitoring of genetic

disorders in order to provide data on the validity of tests and post-

test interventions. It should establish procedures for tracking healthy

individuals with positive test results, as well as those diagnosed with

inherited disorders, to learn more about (1) test validity, (2) the

natural history of such disorders, and the (3) safety and effectiveness

of interventions. The collection of this data should be undertaken in

cooperation with local providers and consultants in genetics and other

relevant specialties. At all times the confidentiality of the data

collected must be protected.

For tests for which long periods of data collection are needed, FDA

should grant conditional premarket clearance or approval before all

necessary data are collected to make promising new technologies

available to the public and enable test developers to obtain an

adequate return on their investment in test development. Developers

would be responsible for continuing to collect data as in the premarket

phase and make it available to FDA. When sufficient data are collected,

FDA will decide whether or not to grant unconditional approval.

Conditional premarket approval should be granted to tests when FDA

considers it likely that the test will prove to make an important

contribution to the prevention or management of the disorder. Under

this circumstance, third-party payers, including government programs

such as Medicare, Medicaid, and CHAMPUS, should reimburse for the test

once it has been conditionally approved. Managed care organizations

should also cover tests given conditional approval.

Technology assessment. Many tests currently on the market have not

been systematically validated nor subject to external review. New tests

that go through these processes will be modified under clinical

conditions.

Technology assessment is important to guide providers and consumers

in the use of genetic tests, but is unlikely to be undertaken by

existing technology assessment agencies because genetic tests do not

entail huge expenditures of health care dollars. NGB should serve as a

clearinghouse for technology assessments of genetic tests that are

about to enter, or already are used in, clinical practice. It could

secure and coordinate assessments of those technologies it considers in

need of stringent scrutiny and coordinate assessments to avoid

unnecessary duplication. NGB could also make recommendations on

appropriate use of genetic tests with input from relevant professional

societies as well as consumer groups.

Assuring Laboratory Quality

The Task Force is concerned about the lack of Federal law or

regulation covering genetic tests except for cytogenetic tests,

limitations of existing voluntary quality assurance and proficiency

testing programs, inadequate assessment of the pre-and post-analytic

phases of testing, and the absence of public information about

laboratories satisfactorily performing genetic tests under existing

voluntary assessments.

CLIA has no standards specific to genetic tests except for

cytogenetics. Currently New York State requires certification of all

laboratories performing clinical genetic tests on state residents. The

College of American Pathologists/American College of Medical Genetics''

(CAP/ACMG) Molecular Pathology accreditation program is also designed

to assess performance on the special problems of genetic tests, placing

greater emphasis on the pre-and post-analytic phases of testing than

other programs. However, CLIA-certified laboratories performing genetic

tests are not required to be assessed by the CAP/ACMG program. If they

are not, genetic tests could be accredited under CLIA without being

specifically assessed. Furthermore, laboratories that participate in

CAP/ACMG's Molecular Pathology program do so voluntarily and not under

CAP's regulatory (``deemed'') authority under CLIA. (Under CLIA, HCFA

has the authority to grant deemed status equivalence to an outside

organization that has a quality assurance and proficiency testing

survey program with standards equal to or greater than CLIA's. CAP's

general proficiency testing program has been ``deemed'' equivalent by

HCFA.) As CLIA has not established standards specifically for genetic

tests, it has no authority to approve the CAP/ACMG Molecular Pathology

program.

Differences between state law and Federal laws and regulations (and

among different nations), create overlapping and often duplicative

requirements for laboratories. The Task Force recommends that a

national accreditation program of quality assurance and proficiency

testing for genetic tests equivalent to or more stringent than those of

New York State and CAP/ACMG, should be established under CLIA. This

accreditation program should include proficiency testing and inspection

of laboratories performing genetic tests. Quality assurance includes:

(a) The skill and training of laboratory staff; (b) evidence of

successful execution of the complex techniques involved in genetic

testing to produce a correct and verifiable test result; and (c)

assessment of pre-testing and post-analytic phases of testing.

Until such time as a national accreditation program is established

under CLIA, the CAP/ACMG Molecular Pathology program, expanded to

encompass all methods currently in use in genetic testing, might itself

serve as the national program, and should be accessible to any

laboratory providing clinical genetic testing. When a national program

is established the CAP/ACMG Molecular Pathology program should have

deemed status.

The Task Force recommends the establishment of a Genetics Advisory

Committee to the Clinical Laboratory Improvement Advisory Committee

(CLIAC) to help address the deficiencies of CLIA in assuring the

quality of genetic tests. The work of this genetics committee should be

reported to the Advisory Committee on Genetics and Public Policy

through the interagency group previously discussed. The work of the

proposed CLIAC advisory committee should also be coordinated with other

HCFA programs, as well as FDA, CDC, and other Federal agencies involved

setting genetic testing policies.

Pre-test education and post-test counseling components of clinical

laboratory tests are critically important parts of the laboratory test

to physicians who are not generally well informed about genetic tests.

Preanalytic components include the information about the test that

laboratories make available to providers and consumers and the informed

consent documents and processes that laboratories may require.

Postanalytic components include the information (interpretation) given

with the test result and counseling services provided or arranged by

laboratories. In any quality assurance program, closer scrutiny is

needed of pre-and post-test analytic components of genetic testing than

current assessment programs provide. The Task Force recommends that

CAP/ACMG seek advice and input from consumer groups such as the

Alliance of Genetic

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Support Groups, as well as from the National Society of Genetic

Counselors (NSGC), on standards for the quality of pre-and post-

analytic components of genetic testing.

The Task Force recommends that CAP/ACMG periodically publish, and

make available to the public, a list of laboratories performing genetic

tests satisfactorily under its voluntary program. The Task Force

recognizes that CAP is not currently required to publish, and has not

published, the names of laboratories performing satisfactorily in the

CAP/ACMG voluntary Molecular Pathology program. Until such time as a

program is established under CLIA, publication will enable providers

and consumers to select approved laboratories and will also serve as an

incentive for laboratories to participate in the CAP/ACMG quality

assessment program. This information should be disseminated using the

Internet and other media accessible to consumers and providers.

Managed care organizations and other third-party payers should

limit reimbursement for genetic tests to the laboratories on the

published list of those satisfactorily performing genetic tests.

Implementation of this recommendation will be especially important as

more managed care organizations move to restrict access to laboratory

services for their members to a single contracted laboratory (which may

or may not be on the list of qualified laboratories).

The Task Force recommends that efforts should be made to harmonize

international laboratory standards to assure the highest possible

laboratory quality for genetic tests. At present, no mechanism exists

to create international standards of laboratory quality and proficiency

for genetic tests. Current United States regulations require any

foreign laboratories performing clinical laboratory tests on U.S.

residents to hold a CLIA certificate even if their nation's laboratory

standards are more stringent that those of CLIA (e.g., as is the case

with Canada).

Provider Competence

The Task Force wants to ensure that non-geneticist providers

adequately appreciate many of the general issues that should be

considered and discussed in offering, providing, and interpreting

predictive genetic tests. These issues include: (1) Who should be

offered a specific test; (2) the benefits and risks of each test; (3)

the need for, and the content of informed consent, and how consent

should be administered; (4) an explanation of test results; and (5)

familiarity with genetic counseling strategies and principles. A

provider's need for knowledge is particularly keen when tests are in

transition from research to clinical use and when clinical utility is

still under investigation and there are no established practice

guidelines.

The Task Force endorses the recent establishment of a National

Coalition for Health Professional Education in Genetics by the American

Medical Association, the American Nurses Association, and the NCHGR.

The Coalition should work in consultation with its member

organizations, including non-genetics professional societies, to

encourage the development of core curricula in genetics, with an

emphasis on having individual professional organizations determine

their own needs in the design and execution of the programs. It should

also encourage input by consumers in the development of these

curricula. The Coalition should serve as a registry of, and

clearinghouse for, information about various curricula and educational

programs, grants, and training pilot programs in genetics education. By

providing educational resources, it should encourage professional

societies to track the effectiveness of their respective educational

programs. The Coalition should disseminate information on available

programs in order to avoid inefficient duplication.

The Task Force strongly recommends that board examinations used for

physician and specialty certification increase both the quality and the

quantity of questions related to genetics. This should further

stimulate the teaching of genetics to medical students, as well as

residents in many specialties. The scores on these questions should

serve as feedback to improve curricula.

Ultimately, implementation of these first two recommendations will

improve the provision of care. The remaining recommendations are

directed at short-term needs.

For those specialties which both require periodic passage of an

examination for recertification and whose practitioners are likely to

order predictive genetic tests, examinations for recertification should

include questions on medical genetics and genetic testing, including

predictive testing.

Hospitals and managed care organizations should use credentialing

and other mechanisms (such as prior authorization) to limit the

offering of certain predictive genetic tests to genetic health care

professionals and physicians who have demonstrated their competence in

dealing with the issues enumerated above. Successful completion of

continuing education courses could be required to demonstrate

competence. (The National Coalition for Health Professional Education

in Genetics should be able to provide information on available programs

for learning about the relevant issues.)

Predictive genetic tests requiring stringent scrutiny, as

previously described, should be among those for which special

credentials are needed. As professional experience is gained with tests

for certain disorders, special credentialing may no longer be required,

but other new genetic tests may take their place. Third-party payers

could also establish policies that allow only properly credentialed

providers to be reimbursed for their role in providing tests.

The Task Force is of the opinion that primary care providers and

other non-geneticist specialists can and should be involved in genetic

testing. However, they must first gain sufficient familiarity with the

issues involved. In some cases, providers should work closely with

genetic health care professionals who can serve as experienced

repositories of in-depth information about many aspects of genetic

testing. Several laboratories already require this collaboration. In

this rapidly changing field, providers should maintain their knowledge

of genetics throughout their professional lives.

Credentialing bodies such as the Joint Commission on Accreditation

of Healthcare Organizations (JCAHO) and the National Committee for

Quality Assurance (NCQA) should assure that hospitals and other health

care organizations develop continuous quality improvement programs

focusing on genetic testing. Systematic and periodic medical record

review, with feedback to providers, is one means of assuring

appropriate use of genetic tests. Such review should assess the extent

to which providers' records for frequently-ordered predictive genetic

tests are in accord with per-determined criteria. These criteria should

include, but not be limited to, appropriate indications for offering

the test, offering the test when it is indicated, and documentation of:

informed consent when appropriate, the test result, information given

to the patient, and the patient's response. Mechanisms should be in

place to assure that review procedures will not infringe on the

confidentiality of the medical records.

Except when time is of the essence, such as with certain prenatal

genetic tests, obtaining informed consent and actually performing the

test should be

[[Page 4547]]

delayed several days after the test is offered and information given to

the patient. This would give people considering testing the opportunity

to absorb information about the test, contemplate the implications of

testing, and discuss testing with others.

Rare Genetic Diseases

Physicians who encounter patients with symptoms and signs of rare

genetic diseases should have access to the best available information

about rare genetic diseases. This will enable them to include such

diseases in their differential diagnosis, to know where to turn for

assistance in clinical and laboratory diagnosis, and to find

laboratories that test for rare diseases. The quality of laboratories

providing tests for rare diseases must be assured, and a comprehensive

system to collect data on rare diseases must be established. Although

these are issues that relate primarily to the diagnosis of patients

with symptoms and signs, they have major implications for predictive

testing in asymptomatic relatives who may be at risk of disease or who

are carriers of alleles for the disease and whose future children may

be at risk.

The Task Force is aware of a number of efforts to address one or

more of these issues, including the availability of disease-based

databases on research projects by the NIH Office of Rare Diseases

(ORD), on information for consumers and providers by the National

Organization of Rare Disorders, the Alliance of Genetic Support Groups

and its member organizations, and by the American Academy of

Pediatrics, and on clinical laboratories providing tests through the

Helix National Directory (available to providers only). In addition,

the Society for Inherited Metabolic Disorders is compiling information

for providers on diagnostic evaluations of rare disorders, and the ACMG

is developing databases on tests that should be used for diagnosis of

specific disorders.

The Task Force recommends that NIH give ORD a mandate to coordinate

these public and private efforts to improve awareness of rare genetic

diseases. Such coordination is important to avoid unnecessary

duplication, to use expertise most efficiently and to address the

concerns of the various groups. ORD could serve as a gateway for

provider and public inquiries about these disorders.

In cooperation with other organizations, and on a regular basis,

ORD should identify laboratories world-wide that perform tests for rare

genetic diseases, the methodology employed, and whether the tests they

provide are in the investigational stage, or are being used for

clinical diagnosis and decision making. Laboratories should notify ORD

about impending cessation of their testing so that provisions for a

transition to other laboratories can be made.

ORD should also be responsible for assuring that tests for rare

genetic diseases, which have been demonstrated to be safe and

effective, continue to be available if and when their developers leave

the field, and no other laboratory is prepared to offer the test, and/

or the methodology is too complex to be readily adopted by other

laboratories. The Task Force urges that additional funds be

appropriated for ORD to undertake this expanded role.

In accordance with current law, the Task Force is of the opinion

that any laboratory performing any genetic test on which clinical

diagnostic and/or management decisions are made should be certified

under CLIA. If specimens must be sent to a non-CLIA licensed research

facility, the referring physician must be made aware of the

investigative nature of the test.

The Task Force recognizes that the current CLIA certification

process may place a heavy burden on some laboratories doing small

numbers of diagnostic tests for rare diseases. Several laboratories

currently performing these tests are primarily engaged in research,

with the tests stemming from their research efforts. Without

accommodation, some tests may cease to be available. Therefore, the

Task Force recommends that the proposed Genetics Advisory Committee to

CLIAC explore means to simplify compliance with CLIA without

sacrificing quality, just as accommodations have been made for rare

genetic disease testing within the New York State Department of Health

laboratory permit process. Recognizing current deficiencies under CLIA

in the assessment of genetic tests (discussed above), the Task Force

also encourages CAP/ACMG to make its clinical accreditation programs

available to low-volume laboratories that are unaffiliated with a

hospital, and modify its procedures to accommodate such laboratories.

Directories of laboratories providing tests for rare diseases

should indicate whether or not the laboratory is CLIA-certified and

whether it has satisfied other quality assessments, such as the CAP/

ACMG program.

The recommendation made earlier, calling on the CDC to expand its

data monitoring capabilities, is intended to include rare diseases.

Collecting data on rare diseases will require coordinating data from

multiple sources. It is particularly needed to validate tests, describe

the natural history of rare diseases and determine the safety and

effectiveness of interventions to prevent disease or ameliorate its

severity.

(Catalogue of Federal Domestic Assistance Program No. 93.172, Human

Genome Research.)

Elke Jordan,

Executive Secretary, National Advisory Council for Human Genome

Research.

[FR Doc. 97-2286 Filed 1-29-97; 8:45 am]

BILLING CODE 4140-01-P