[Federal Register: May 4, 2000 (Volume 65, Number 87)]
[Notices]
[Page 25928-25934]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
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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.
<bullet> Because of the sensitive nature of certain genetic tests,
the laboratory must have assurance that the ``authorized'' person has
obtained informed consent.
<bullet> 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.
<bullet> 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.
<bullet> 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:
<bullet> 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)
<bullet> 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.
<bullet> 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]]
<bullet> 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.
<bullet> 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
<bullet> A specimen should be stabilized until the clinical
information for accurate testing is available.
<bullet> The laboratory must be designed to minimize contamination.
<bullet> Amplification procedures which are not in wholly closed
systems must have separation between preparative and post-amplification
steps.
<bullet> Work processes must minimize risk of mixing samples, and
risk of
[[Page 25934]]
contamination of equipment, reagents, and/or supplies.
<bullet> RNA work areas must be separated from DNA work areas.
Specimen Integrity
<bullet> 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:
<bullet> Laboratories must verify or establish reproducibility for
each method within and between runs, and between technologists.
<bullet> Methodology must be appropriate for conditions being
evaluated.
<bullet> Quality control parameters must be applicable.
<bullet> Reagents must be validated.
Clinical Validation: Laboratories must consider the following
clinical parameters for test validation:
<bullet> A positive confirmatory test must have a defined positive
predictive value which can be communicated to the care giver.
<bullet> 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.
<bullet> 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:
<bullet> 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.
<bullet> When individual interpretation of the test result is
required, the signature of the Director or designee must appear on the
report.
<bullet> A means to quickly contact the Laboratory Director/
Technical Supervisor, in addition to address, must be indicated on the
report.
<bullet> Any reference to family members in a test report must
utilize standardized pedigree nomenclature or numeric indicators,
instead of individual names.
<bullet> 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:
<bullet> 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.
<bullet> 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