[Federal Register Volume 65, Number 87 (Thursday, May 4, 2000)]
[Notices]
[Pages 25928-25934]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-11093]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention


Notice of Intent; Genetic Testing Under the Clinical Laboratory 
Improvement Amendments

SUMMARY: The Centers for Disease Control and Prevention (CDC) acts as a 
scientific advisor to the Health Care Financing Administration (HCFA) 
in development of requirements for clinical laboratories under the 
Clinical Laboratory Improvement Amendments (CLIA). The CDC is issuing 
this notice to advise the public that the Department of Health and 
Human Services (HHS) will be preparing a Notice of Proposed Rule Making 
(NPRM) to revise the CLIA regulations applicable to laboratories 
performing human genetic testing. Before issuing the NPRM, comments are 
being solicited on the recommendations of the Clinical Laboratory 
Improvement Advisory Committee (CLIAC) to change current CLIA 
requirements to specifically recognize a genetic testing specialty. 
This new speciality area will address unique testing issues in the pre-
analytic, analytic, and post-analytic phases of testing that could 
affect the accuracy and reliability of test results, and related issues 
such as informed consent, confidentiality, counseling, and the clinical 
appropriateness of a genetic test. To ensure that a full range of 
issues relating to this proposed action are addressed and potential 
impacts are identified, comments and suggestions are invited from all 
interested parties. Comments or questions regarding this proposed 
action should be directed to CDC at the address below.
    The Department has also established a Secretary's Advisory 
Committee on Genetic Testing (SACGT) to advise the Department on the 
medical, scientific, ethical, legal, and social issues raised by the 
development and use of genetic

[[Page 25929]]

testing. The SACGT is currently addressing, in consultation with the 
public, broad questions related to the adequacy of oversight of genetic 
testing. If, after public consultation and analysis, SACGT finds that 
further oversight measures are warranted, it will recommend options for 
such oversight. The public comment for the SACGT issues is being 
conducted separately (See the December 1, 1999 Federal Register, 64 FR 
67273). The reason for independent solicitations is that the SACGT is 
addressing more general aspects of genetic testing, such as the 
criteria that should be used to assess the benefits and risks of 
genetic tests. That purpose differs from this solicitation that deals 
specifically with the application of CLIA to genetic laboratory 
testing. The two requests for public comments thus solicit 
complementary information: the SACGT comments will guide development of 
recommendations to the Secretary on policy and oversight issues, 
whereas comments on the CLIAC recommendations will guide development of 
appropriate genetic testing laboratory requirements for revision of the 
CLIA regulations.

DATES: Written comments received by July 3, 2000, will be incorporated 
into the record.

ADDRESSES: Send comments to D. Joe Boone, Ph.D., Assistant Director for 
Science, Division of Laboratory Systems, Public Health Practice Program 
Office, Centers for Disease Control and Prevention, 4770 Buford 
Highway., N.E., Mailstop G25, Atlanta, Georgia 30341, at telephone 
(770) 488-8080.

SUPPLEMENTARY INFORMATION:

Background

A. Human Genetic Testing

    Human genetic testing involves the analysis of chromosomes, 
dioxyribonucleic acids (DNA), ribonucleic acids (RNA), and genes and 
gene products (e.g. proteins and enzymes) to detect heritable or 
acquired disease-related disorders or conditions. Federal and private-
sector human genome projects will soon decipher the structure for the 
100,000 to 140,000 genes residing on the 23 pairs of human chromosomes. 
It is expected that along with this definition of structure will come 
associations between the variations in gene structure and a variety of 
conditions and diseases. Once associations have been delineated, the 
use of genetic testing is expected to expand significantly to determine 
whether an individual has a condition or disease or might develop a 
condition or disease in the future.
    Human genetic testing is expected to lead to a whole new era in 
health care. Some tests may determine not only whether an individual 
has a particular disease or condition, but also may determine their 
risk of developing a disease or condition in the future. However, along 
with the tremendous potential for improving health and preventing 
disease, genetic testing can also do great harm if errors occur in: (1) 
The selection of an appropriate test, (2) the performance of the test, 
(3) the interpretation of the tests results, or (4) the clinical 
application of the test results. False-positive or false-negative 
results can be especially troublesome when the test is being used to 
predict future risk of disease in an individual without any current 
symptoms of disease.
    The process of performing a genetic test can be broken into three 
distinct phases: (1) The pre-analytic phase, which encompasses such 
events as determining which genetic test, if any, is appropriate to 
answer the clinical question being asked and collecting an appropriate 
sample and transporting it to the test site; (2) the analytical phase, 
which involves steps taken to perform the analysis and analyze the 
results; and (3) the post-analytic phase, which includes reporting and 
interpretation of the results. It is important to recognize that the 
laboratory may need to be involved in carrying out or assisting with 
all three phases of testing and that errors can occur either within the 
laboratory or at the interface between the laboratory and the care 
provider.
    In the pre-analytic phase, one recent study found that 20 percent 
of adenomatous polyposis coli (APC) genetic tests were ordered for 
inappropriate indications and 19 percent of patients received genetic 
counseling before testing occurred (Giardiello FM, et al. The use and 
interpretation of commercial APC gene testing for familial adenomatous 
polyposis. N Engl J Med 1997;336:823-827). Another recent survey of 245 
molecular genetic testing laboratories found that 55 percent of the 
laboratories did not require informed consent prior to testing and 31 
percent did not have a written policy on confidentiality (McGovern MM, 
et al. Quality assurance in molecular genetic testing laboratories. 
JAMA 1999;835-840). This same study found what the authors considered 
to be substandard laboratory practice, which could lead to adverse 
clinical outcomes, in 15 percent of the laboratories. In the post-
analytic phase of testing, the Giardiello study reported that 31 
percent of the cases were misinterpreted by the physician. The McGovern 
study found that 30 percent of laboratories did not provide access to 
genetic counseling.
    These and other studies point to the need for improvements in 
laboratory practice and better coordination between the care provider, 
laboratory, genetic counselor, and the patient to ensure quality in 
genetic testing. The HHS has sought the advice of experts in laboratory 
medicine and genetic testing to help identify places in the testing 
process where testing problems are most likely to occur, and to 
determine what modifications to current CLIA regulations could provide 
greater assurance of accurate and reliable testing. Issues for which 
the laboratory might provide additional assistance to the laboratory 
user such as informed consent, counseling, and protecting 
confidentiality were also considered. The recommendations below were 
developed during a series of public meetings of the Clinical Laboratory 
Improvement Advisory Committee (CLIAC).

B. Current Roles of Government and Professional Organizations in 
Genetic Testing

    In considering whether to create a genetic specialty under CLIA and 
whether to include the provisions recommended by the CLIAC, it is 
important to understand the current roles of government and 
professional organizations in genetic testing, and to note that no 
single agency or organization is likely to be able to address all of 
the issues raised by genetic testing.
    Genetic tests are currently 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 of test development, under applicable 
regulations for the Protection of Human Subjects (45 CFR 46, 21 CFR 50, 
and 21 CFR 56). In addition, some States regulate and private-sector 
organizations monitor genetic testing laboratories.
    On October 31, 1988, Public Law 100-578, Clinical Laboratory 
Improvement Amendments of 1988 (CLIA), Section 353 of the Public Health 
Service Act, (42 U.S.C. 263a) was enacted. On February 28, 1992 (57 FR 
7002), HHS published a final rule applicable to all laboratories that 
examine human specimens to provide information for the diagnosis, 
prevention, or treatment of any disease or impairment of, or assessment 
of the health of, human beings. (Note: Facilities that only perform 
testing for forensic purposes and research

[[Page 25930]]

laboratories that test human specimens but do not report patient 
specific results are exempt from the CLIA regulations.)
    Under CLIA, laboratories are required to meet specific requirements 
before they can become CLIA-certified. Regulated tests are categorized 
according to their level of complexity: waived, moderate, and high 
complexity, with the regulatory requirements increasing in stringency 
with the complexity of the tests performed. Under CLIA, the Health Care 
Financing Administration (HCFA) in partnership with CDC develops 
standards for laboratory certification. The advice of the HHS Clinical 
Laboratory Improvement Advisory Committee (CLIAC) may also be sought. 
Laboratories performing non-waived tests receive on-site inspections 
conducted by HCFA or by designated organizations or State-operated CLIA 
programs.
    Overall monitoring includes a comprehensive evaluation of the 
laboratory's operating environment, personnel, proficiency testing, 
quality control, and quality assurance. Laboratory directors are 
required to take specific actions to establish a comprehensive ongoing 
quality assurance program, which ensures that the 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 specimen analysis and reporting of the 
results), CLIA oversight emphasizes intralaboratory processes as 
opposed to the clinical uses of test results.
    All laboratory testing devices, kits and their components are 
subject to FDA oversight under the Federal Food, Drug, and Cosmetic 
Act. Testing devices and tests that are packaged and sold as kits to 
multiple laboratories require premarket approval or clearance by the 
FDA. This premarket review involves an analysis of the device's 
accuracy as well as its analytical sensitivity and specificity. 
Premarket review is performed based on data submitted to FDA's 
scientific reviewers. In addition, for devices for which the link 
between clinical performance and analytical performance has not been 
well established, FDA requires additional analyses to determine the 
test's clinical characteristics, or its clinical sensitivity and 
specificity. In some cases, FDA requires that the predictive value of 
the test be analyzed.
    The majority of new genetic tests are being developed by 
laboratories for their own use, that is, in-house tests. The FDA 
established a measure of regulation of in-house tests by instituting 
controls over the active ingredients (analyte-specific reagents) used 
by laboratories to perform tests. This regulation subjects reagent 
manufacturers to certain general controls, such as good manufacturing 
practices; however, with few exceptions, the current regulatory process 
does not require a premarket review of these reagents. The regulation 
requires that the sale of reagents be only to laboratories capable of 
performing high-complexity tests and requires that certain information 
accompany both the reagents and the test results. The labels for the 
reagents must also 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 in-house developed tests to consumers.
    Human subjects participating in the research phase of development 
of a genetic test are under the protection of human research subjects 
regulations administered by the National Institutes of Health (NIH) and 
the FDA. NIH oversees the protection of human research subjects in HHS-
funded research, while the FDA oversees the protection of human 
research subjects in trials of investigational (unapproved) devices, 
drugs, or biologics being developed for eventual commercial use. 
Fundamental requirements of these regulations are that experimental 
protocols involving human subjects be reviewed by an organization's 
Institutional Review Board (IRB) to assure the safety of the subjects 
and that risks do not outweigh potential benefits.
    Some State agencies may monitor laboratories performing genetic 
testing, including licensure of personnel and facilities. In some 
instances, the State Public Health Laboratory and State-operated CLIA 
program are responsible for quality assurance activities. A few States, 
such as New York, 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.
    Private-sector organizations, in partnership with HCFA and CDC may 
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 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 consensus 
recommendations for the standardization of test methodologies; and the 
American College of Medical Genetics (ACMG), which develops guidelines 
for the use of particular tests and test methodologies and works with 
the CAP to provide proficiency tests for certain genetic tests. Other 
organizations, such as the American Academy of Pediatrics, American 
College of Obstetrics and Gynecology, American Society of Human 
Genetics, and National Society of Genetic Counselors, are also involved 
in the development of guidelines and recommendations regarding the 
appropriate use of genetic tests.
    Presently, no federal agency has specifically addressed other 
aspects of oversight that are critical to the appropriate use of a 
genetic test, including the clinical validity and clinical utility of a 
given test. Also not addressed are other important issues such as 
informed consent and genetic counseling.

C. Proposed Changes to CLIA Laboratory Regulations

    Currently, CLIA has very specific requirements for certification of 
laboratories in areas such as cytology, microbiology, and clinical 
cytogenetics; a specialty category of genetics does not currently exist 
even though genetic testing is covered under the general provisions of 
CLIA. If a genetics specialty category is created, genetic testing will 
need to be defined (see definitions under question 1).

Recommendations of Clinical Laboratory Improvement Advisory 
Committee (CLIAC)

    On September 11, 1997, January 29, 1998, May 28-29, 1998, September 
17-18, 1998, and September 22-23, 1999 the CLIAC met to develop 
recommendations on how the CLIA regulation might be modified to address 
genetic testing. Summary accounts of the meetings at which these 
recommendations were developed can be found at the CDC website at 
http://www.phppo.cdc.gov/dls/cliac/default.asp. The CLIAC's 
deliberations provide definitions for laboratories performing genetic 
testing; address issues in the pre-analytic, analytic, and post-
analytic phases of testing; and describe how a laboratory's 
responsibilities and those of the care

[[Page 25931]]

provider, genetics counselor, and individual being tested are related.
    While these recommendations were developed by experts in the field 
of genetics and laboratory aspects of genetic testing, we are 
interested in determining the impact of imposing the specific 
requirements recommended by CLIAC on the wide spectrum services offered 
by the nation's 170,000 clinical laboratories. We are interested in 
determining which, if any, of these recommendations might prove 
problematic to low volume laboratories, which may be the only source of 
a specific genetic test. Finally, we are interested in receiving 
comments about whether implementing these recommendations would 
increase, decrease, or have no effect on the quality of, access to, or 
cost of genetic testing services.
    Please note that genetic testing laboratories are already subject 
to the current personnel, quality assurance, quality control, and 
patient test management provisions of CLIA (42 CFR Part 493). Also note 
that the recommendations have been divided into topics which apply 
globally to all phases of genetic testing, and those specific to the 
pre-analytic, analytic, and post-analytic phases of testing.
    While this Notice of Intent requests comments on a range of 
laboratory issues related to potential regulation of genetic testing 
recommended by the CLIAC, the Department has not yet determined whether 
the scope of CLIA will allow regulation of all of these issues.

CLIA Questions on Which Comment Is Being Solicited

    The CLIAC has made recommendations on the issues listed below. We 
are interested in receiving comments on the following questions which 
arise when considering the adoption of these recommendations under the 
regulatory provisions of CLIA.

General Requirements

    Note: These issues apply to more than one phase of the testing 
process.

1. Are the Following Definitions for Categories of Genetic Testing To 
Be Covered Under a New CLIA Specialty of Genetics Appropriate (or Too 
Broad or Too Restrictive)?
    A. Current CLIA Requirement: A specialty of genetic testing has not 
been defined under CLIA. However, CLIA already applies to genetic 
testing since it regulates any laboratory that examines human specimens 
to provide information for diagnosis, prevention, or treatment of any 
disease or impairment of, or assessment of the health of, human beings.
    B. CLIAC Recommendation: The CLIAC suggested that the following 
definitions for the specialty of genetic testing be adopted.
    Molecular genetic and cytogenetic test--An analysis performed on 
human DNA, RNA, and chromosomes to detect heritable or acquired 
disease-related genotypes, mutations, phenotypes, or karyotypes for 
clinical purposes. Such purposes would include predicting risk of 
disease, identifying carriers, and establishing prenatal or clinical 
diagnoses or prognoses in individuals, families, or populations.
    Biochemical genetic test--The analysis of human proteins and 
certain metabolites, which is predominantly used to detect inborn 
errors of metabolism, heritable genotypes, or mutations for clinical 
purposes. Such purposes would include predicting risk of disease, 
identifying carriers, and establishing prenatal or clinical diagnoses 
or prognoses in individuals, families, or populations. [Tests that are 
used primarily for other purposes, but may contribute to diagnosing a 
genetic disease (e.g. blood smear, certain serum chemistries), would 
not be covered by this definition.]
    C. Issue: A genetic speciality will be linked to specific personnel 
qualifications and responsibility requirements, as well as proficiency 
testing and quality control provisions (see other recommendations which 
could also be implemented under the specialty). Therefore, inclusion or 
exclusion from the specialty could alter a laboratory's staffing plans, 
reimbursements, and overall costs.
2. What Is the Role of a Laboratory Director in Documenting the 
Clinical Validity of a Genetic Test Their Laboratory Plans To Offer? If 
There is a Role, How Should the Laboratory Director's Documentation of 
the Clinical Validity of a Genetic Test Be Monitored?
    A. Current CLIA Requirement: Under 493.1407 Standard; Laboratory 
director responsibilities, (e) the laboratory director must ensure that 
testing systems developed and used for each of the tests performed in 
the laboratory provide quality laboratory services for all aspects of 
test performance, which includes the pre-analytic, analytic, and post-
analytic phases of testing, ensure that the test methodologies selected 
have the capability of providing the quality of results required for 
patient care, and ensure that verification procedures used are 
adequate. Under 493.1213 Standard; establishment and verification of 
method performance specifications, prior to reporting patient test 
results the laboratory must verify or establish for each method, the 
performance specifications for: accuracy; precision; analytical 
sensitivity and specificity, if applicable; the reportable range of 
patient test results; the reference range; and any other applicable 
performance characteristics.
    B. CLIAC Recommendation: Although the CLIAC considered the scope of 
the current laboratory director responsibilities to be adequate, they 
were concerned about how to monitor the laboratory director's 
documentation of the clinical validity for the tests performed. The 
CLIAC recommended adding specific requirements for analytical and 
clinical validation of tests (see question 7 below).
    C. Issue: Although there are specific requirements for analytic 
validation, no specific requirements for clinical validation have been 
included under CLIA. Clinical validation of all tests, such as 
cholesterol, has been assumed to have been documented before tests are 
offered. Concerns about requiring specific documentation of the 
clinical validity of genetic tests have been expressed, with some 
expressing the view that establishing the clinical validity and 
documenting it for the tests offered are outside of the laboratory's 
purview.
3. Who Should Be Authorized To Order a Genetic Test?
    A. Current CLIA Requirement: Under 493.1105 Standard; Test 
requisition--the laboratory must perform tests only at the written or 
electronic request of an authorized person.

    Note: Under 493.2 Definitions--An authorized person means an 
individual authorized under State law to order tests or receive 
results, or both.

    B. CLIAC Concern: The CLIAC raised the issue that some States 
provide no guidance on this issue.
    C. Issue: Is genetic testing sufficiently different from other 
types of laboratory testing to warrant a new Federal requirement to 
define who is authorized to order a genetic test?
    4. Should the Laboratory Be Required to Document That Informed 
Consent Has Been Obtained by an Authorized Person From the Person Being 
Tested Before Performing Certain Genetic Tests or Types of Tests 
(Screening, Diagnostic, Carrier, Presymptomatic, Susceptibility)?
    A. Current CLIA Requirement: CLIA, at present, does not 
specifically require a laboratory to document that an informed consent 
has been obtained by

[[Page 25932]]

an authorized person before testing is performed.
    B. CLIAC Recommendation: The CLIAC recommended the following 
guidance on this issue.
     Because of the sensitive nature of certain genetic tests, 
the laboratory must have assurance that the ``authorized'' person has 
obtained informed consent.
     At the request of the ``authorized'' person, the 
laboratory shall assist in developing appropriate informed consent for 
the particular test, including the limitations and consequences of the 
test results.

    Note: The National Bioethics Advisory Commission in its August 
1999 report on ``Research Involving Human Biological Materials: 
Ethical Issues and Policy Guidance'' provides guidance to research 
laboratories, which are exempt from CLIA if they do not report 
patient specific results. These recommendations do not apply to 
clinical interventions, quality control, or teaching, but only to 
``a systematic investigation designed to develop or contribute to 
generalizable knowledge.''

    C. Issue: Imposition of this requirement on laboratories could 
serve to protect patients from inappropriate testing, but increases the 
laboratory burden of documentation and could also delay obtaining 
genetic testing results. Are the CLIA regulations an appropriate place 
for regulating informed consent related to genetic testing? Also, how 
do current State medical consent laws factor into this?
    5. Should Additional Processes Be in Place to Enhance the 
Confidentiality of Certain Genetic Test Information and Results?
    A. Current CLIA Requirement: Under 493.1109 Standard; Test report, 
(a)--the laboratory must have adequate systems in place to report 
results in a timely, accurate, reliable, and confidential manner, and, 
ensure patient confidentiality throughout those parts of the testing 
process that are under the laboratory's control.
    B. CLIAC recommendation: The CLIAC recommended the following 
guidance on this issue.
     Due to the sensitive nature of certain genetic test 
results, the laboratory must have a policy in place to protect the 
confidentiality of test result reporting.
     All requests for additional tests must follow 
confidentiality and informed consent requirements (see above).

    Note: HHS under the Health Insurance and Portability and 
Accountability Act (HIPAA) published in the Federal Register on 
November 3, 1999 a proposed rule Standards for Privacy of 
Individually Identifiable Health Information. This rule applies to 
individually-identifiable health information that has been 
electronically transmitted or maintained. The NPRM is accessible at 
(http://www.aspe.hhs.gov/admnsimp/).

    C. Potential implication of the CLIAC issue: This would not impose 
an additional requirement on laboratories, but would clarify that a 
policy must be in place for the genetic specialty. Is being this 
explicit for genetic testing necessary?
6. Assuming That a Genetic Specialty Under CLIA Is Defined and 
Recognized, Should a Laboratory Covered Under This Specialty Be 
Required To Provide Genetic Counseling to Their Clients (Including 
Medical Care Providers and Patients), for the Tests They Offer?
    A. Current CLIA Requirement: Under 493.1419/493.1457 Standard; 
Clinical Consultant responsibilities--laboratories are required to have 
a qualified clinical consultant to provide consultation regarding the 
appropriateness of the testing ordered and interpretation of test 
results. The consultant must be available to provide consultation and 
to assist in ensuring that appropriate tests are ordered to meet 
clinical expectations, and ensure that reports of test results include 
pertinent information required for specific patient interpretation, and 
that matters related to the quality of test results are communicated.
    B. CLIAC Recommendation: The CLIAC recommended that the 
qualifications and responsibilities of the clinical consultant be 
expanded to assure that someone associated with the laboratory be 
capable of providing genetic counseling to the laboratory's clients 
(care providers, patients, individuals, etc.).
    Clinical Consultant--Be an M.D., D.O., and have two years 
experience in genetic testing.; or hold a Ph.D. in a relevant 
discipline, be Board certified, and have two years experience in 
genetic testing; or hold an MS in Genetic Counseling, be Board 
certified, and have two years experience in genetic testing 
(prospective).
    Clinical Consultant--For genetic testing, require that the Clinical 
Consultant assist clients in ordering appropriate tests to meet 
clinical needs.
    C. Issues: Will there be a sufficient number of qualified clinical 
consultants available and is the experience mentioned necessary for all 
types of genetic tests? Will care providers request/accept assistance 
in ordering genetic tests? What should the role of the laboratory be in 
counseling providers and/or patients. Does it extend to family members?

Requirements Related to Specific Phases of the Testing Process

    These issues apply to one phase of the testing process.
7. Should the Following Requirements Be Added Under a Specialty of 
Genetics to CLIA To Address Unique Aspects of Laboratory Responsibility 
for Genetic Testing?
Pre-Analytic Phase
Obtaining Clinical Information on the Test Requisition and the Ordering 
of Additional Tests
    A. Current CLIA Requirement: Under 493.1419/493.1457; Standard; 
Clinical Consultant responsibilities--laboratories are required to have 
a qualified clinical consultant to provide consultation regarding the 
appropriateness of the testing ordered and interpretation of test 
results. The consultant must be available to provide consultation and 
to assist in ensuring that appropriate tests are ordered to meet 
clinical expectations, and ensure that reports of test results include 
pertinent information required for specific patient interpretation, and 
that matters related to the quality of test results are communicated. 
Also under 493.1105, Standard; Test Requisition, (f)--the laboratory 
must assure that the requisition or test authorization includes any 
additional information relevant and necessary to a specific test to 
assure accurate and timely testing and reporting.
    B. CLIAC recommendation: Test Requisition and ordering additional 
tests:
     Appropriate clinical information to ensure accurate and 
reliable genetic testing must be provided with the test request.

    Note: In some instances very explicit information may be 
required to decide which test method to use and to appropriately 
interpret the results. Such information would include all that is 
relevant and necessary to ensure accurate and timely testing, 
interpretation and reporting of results and elements to ensure 
proper identification of the subject being tested. Relevant 
information for a genetic test may include date of birth, gender, 
ethnicity, and/or family history)

     When deemed necessary, the laboratory shall assist those 
ordering tests by suggesting follow-up tests, when appropriate, to 
expedite the function of obtaining relevant clinical information.
    Re-Use of Tested Specimens.
     When patient identifiers are not removed from the 
specimens, informed consent must be obtained prior to re-use of 
previously tested specimens for quality control (QC) and quality 
assurance (QA) purposes.

[[Page 25933]]

     When the laboratory intends to re-use previously tested 
specimens without patient identifiers for QC and QA, it must have a 
procedure that permits patients with a personal objection to other uses 
of their specimen to be able to elect not to have their specimen used 
for these purposes.
     The use of a retained sample does not require informed 
consent if all identifiers are removed and the patient has had an 
opportunity to decline being tested.
    C. Issue. The laboratory may require additional patient information 
in order to make decisions about which specific tests or additional 
tests would be most useful to provide the needed clinical information. 
However, this information may be difficult to obtain in every instance. 
With respect to additional testing, coverage or payment for testing may 
be an issue. The conditions under which testing specimen may be re-used 
for quality control is generally accepted as good laboratory practice, 
but not explicitly provided for under current requirements.
Analytic Phase
Personnel Qualifications
    A. Current CLIA Requirement: Under Subpart M--Personnel for High 
Complexity Testing:
    Laboratory Director--Be an M.D. or D.O. or DPM with certification 
in clinical and/or anatomic pathology; or be a Ph.D. and be certified 
by a board approved by HHS; or be an M.D. or D.O. and have two years 
directing or supervising high complexity testing; or hold a doctorate 
degree in a chemical, physical, biological, or clinical laboratory 
science, be certified, and have two years of supervisory experience in 
high complexity testing; or be grandfathered.
    Technical Supervisor--Although no genetic specialty currently 
exists, the following technical supervisor requirements apply to the 
specialty of cytogenetics.--Be an M.D., D.O. or DPM with four years of 
training or experience in genetics, two of which have been in clinical 
cytogenetics; of Ph.D. with four years of training or experience in 
genetics, two of which have been in clinical cytogenetics.
    General Supervisor--Be qualified as a laboratory director or 
technical supervisor; or be an M.D., D.O., DPM, or have a Doctorate, 
Masters or Baccalaureate degree in a chemical, physical, biological or 
clinical laboratory science, and have one year training or experience 
in high complexity testing; or have an Associate degree, or equivalent, 
in a chemical, physical, biological or clinical laboratory science and 
have two years training or experience in high complexity testing; or be 
grandfathered.
    Clinical Consultant--Be qualified as a laboratory director or be an 
M.D., D.O., DPM and licensed to practice medicine in the State in which 
the laboratory is located.
    B. CLIAC recommendation: To the current requirements listed above, 
add the following:
    Laboratory Director--Be an M.D. or D.O. or DPM with certification 
in clinical and/or anatomic pathology; or be an M.D., D.O., or Ph.D. 
and be certified in medical genetics by a board approved by HHS; or be 
an M.D. or D.O. and have two years directing or supervising high 
complexity testing; or hold a doctorate degree in a chemical, physical, 
biological, or clinical laboratory science, be certified, and have two 
years of supervisory experience in high complexity testing; or be 
grandfathered
    If a genetic specialty is developed, the CLIAC recommended the 
following personnel qualifications.
    Technical Supervisor--Be an M.D. or D.O. with certification in 
clinical and/or anatomic pathology plus two years sub-specialty 
training in genetics and have two years supervisory experience in high 
complexity genetic testing, or have four years supervisory experience 
in high complexity genetic testing in the relevant subspecialty; or be 
an M.D., D.O. or Ph.D. and be certified in the appropriate medical 
genetics specialty and have two years experience directing or 
supervising high complexity genetic testing in the relevant 
subspecialty; or hold a doctorate degree in a chemical, physical, 
biological, or clinical laboratory science, and have four years of 
training or supervisory experience in high complexity genetic testing 
in the relevant subspecialty; or be grandfathered.
    General Supervisor--Be qualified as a laboratory director or 
technical supervisor; or be an M.D., D.O., hold a Doctorate or Masters 
degree in a chemical, physical, biological or clinical laboratory 
science, and have two years experience in high complexity genetic 
testing; or hold a Baccalaureate degree in a chemical, physical, 
biological or clinical laboratory science and have three years 
experience in high complexity genetic testing; or be grandfathered.
    Clinical Consultant--Be an M.D., D.O., and have two years 
experience in genetic testing.; or hold a Ph.D. in a relevant 
discipline, be Board certified, and have two years experience in 
genetic testing; or hold an MS in Genetic Counseling, be Board 
certified, and have two years experience in genetic testing 
(prospective).
    C. Issue: Could assure higher quality in genetic testing, but could 
restrict who could serve in these personnel categories. The extent of 
the impact is dependent upon the tests included in the definition of 
the genetic specialty.
Personnel Responsibilities
    A. Current CLIA Requirements: See Subpart M of 42 CFR Part 493.
    B. CLIAC Recommendations. To the current requirements, add the 
following:
    Technical Supervisor--The Technical Supervisor (in addition to the 
Laboratory Director and Clinical Consultant currently required under 
CLIA) must ensure that reports include pertinent information required 
for clinical interpretation that is meaningful to a non-geneticist 
health care provider.
    Clinical Consultant--For genetic testing, require that the Clinical 
Consultant assist clients in ordering appropriate tests to meet 
clinical needs.
    C. Issue: Could assure higher quality in genetic testing, but could 
be difficult for all laboratories to acquire the personnel with the 
skills needed.
Quality Control and Patient Test Management
    A. Current CLIA Requirement. Under 493.1105 Standard; Test 
requisition and 493.1107 Standard; Test records a laboratory must 
ensure that the requisition or test records include patient's name or 
unique identifier and laboratory number; date of collection and receipt 
in the laboratory. Under 493.1213 Standard; establishment and 
verification of method performance specifications, prior to reporting 
patient test results the laboratory must verify or establish for each 
method, the performance specifications for: accuracy; precision; 
analytical sensitivity and specificity, if applicable; the reportable 
range of patient test results; the reference range; and any other 
applicable performance characteristics.
    B. CLIAC Recommendation. The CLIAC recommended that the following 
new provisions be added:
Quality Control/Contamination
     A specimen should be stabilized until the clinical 
information for accurate testing is available.
     The laboratory must be designed to minimize contamination.
     Amplification procedures which are not in wholly closed 
systems must have separation between preparative and post-amplification 
steps.
     Work processes must minimize risk of mixing samples, and 
risk of

[[Page 25934]]

contamination of equipment, reagents, and/or supplies.
     RNA work areas must be separated from DNA work areas.
Specimen Integrity
     Requirements to ensure identification of the subject being 
testing include: date of birth; gender; ethnicity; patient or family 
number; specimen source; time of collection; and name of person 
obtaining sample
Validation of Tests
    Analytic validation:
     Laboratories must verify or establish reproducibility for 
each method within and between runs, and between technologists.
     Methodology must be appropriate for conditions being 
evaluated.
     Quality control parameters must be applicable.
     Reagents must be validated.
    Clinical Validation: Laboratories must consider the following 
clinical parameters for test validation:
     A positive confirmatory test must have a defined positive 
predictive value which can be communicated to the care giver.
     Where the disease prevalence is more frequent than 1/
10,000, the validity must be documented in at least 10 positive 
probands (including cell lines or DNA/RNA) prior to offering the test.
     Predictive value should be defined in terms of ethnic 
populations, when applicable
    C. Issue: These recommendations are based on what the CLIAC 
considers to be good laboratory practice in genetic testing. They 
represent extensions to existing requirements to specifically address 
some of the unique aspects of genetic testing. Are these sufficiently 
comprehensive, adequate, or are they not needed?
Proficiency Testing (PT)
    A. Current CLIA Requirement: Under 493.801 Condition; Enrollment 
and testing of samples--a laboratory must enroll in an approved 
proficiency testing program for each specialty for which it seeks 
certification. Currently, no PT requirement exists, because there is no 
genetic specialty, therefore the following PT requirement applies. 
Under 493.1703 Standard; Comparison of test results--when a laboratory 
performs tests for which PT is unavailable, the laboratory must have a 
system for verifying the accuracy and reliability of its test results 
at least twice a year.
    B. CLIAC Recommendation: The CLIAC recommended including the 
following new provision:
     When an approved PT program does not exist for the test, 
the regulations should require alternatives (to be performed three 
times per year, on five specimens per event). Examples include: Split 
samples sent to another laboratory; blinded test samples; test samples 
in duplicate by separate technologists, in a blinded manner; and other 
equivalent approaches
    C. Issue: Requiring PT would provide a basis for evaluating the 
accuracy of genetic testing.
Post-Analytic Phase
Special Reporting Requirements
    A. Current CLIA Requirement: Under 493.1109 Standard; Test report--
a laboratory must, upon request, make available to clients a list of 
test methods and information that may affect the interpretation of test 
results, such as interferences.
    B. CLIAC Recommendation: Laboratory reports must include the 
following, as applicable, as they relate to the interpretation of the 
test result:
    --Interpretation.
    --Comments.
    --Recommendations for further testing or clinical consultation.
    --Summary of the test method and its limitations.
     When individual interpretation of the test result is 
required, the signature of the Director or designee must appear on the 
report.
     A means to quickly contact the Laboratory Director/
Technical Supervisor, in addition to address, must be indicated on the 
report.
     Any reference to family members in a test report must 
utilize standardized pedigree nomenclature or numeric indicators, 
instead of individual names.
     Specific requirements for reporting molecular genetic 
testing include:
    --A list of the mutant alleles tested.
    --The rate detection of the panel.
    -- A revised assessment of likelihood based on test results, as 
applicable.
    --Important clinical implications for other family members should 
be provided, as applicable.
    --Variables that affect test interpretation (e.g. ethnicity) must 
be specified in the report, and limitations of the testing must be 
defined.
    C. Issue: Requiring laboratories to provide this information could 
increase the accuracy of interpretation of genetic testing reports, but 
may increase the laboratories' burden.
Record/Specimen Retention
    A. Current CLIA Requirement: Under 493.1109 Standard; Test report--
the laboratory must retain the original or an exact duplicate of each 
test report for a period of at least two years after the date of 
reporting.
    B. CLIAC Recommendation:
     Copies of patient reports of genetic testing shall be 
retrievable for a minimum of 10 years, or longer if required by State 
law. Electronic reports are acceptable.
     The laboratory must have a policy defining specimen 
retention policies.
    C. Issue: Maintaining reports for a longer period of time may be 
beneficial but this could be burdensome.

    Dated: April 27, 2000.
Jeffrey Koplan,
Director, Centers for Disease Control and Prevention.
[FR Doc. 00-11093 Filed 5-3-00; 8:45 am]
BILLING CODE 4163-18-P