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To: Multiple recipients of list HUM-MOLGEN <HUM-MOLGEN@NIC.SURFNET.NL>
Subject: DIAG, ETHI: genetic lab standards
From: Hans Goerl <GENETHICS@delphi.com>
Date: Fri, 18 Aug 1995 23:41:52 -0400

Here is the complete discussion of the first meeting of the Task Force on
Genetic Testing. It will shortly be available on HUM-MOLGEN'S www site.

Hans Goerl, ETHI Editor


of the NIH-DOE Working Group on Ethical, Legal, and Social Implications
(ELSI) of the Human Genome Project

550 N. Broadway, Suite 511
Baltimore, Maryland 21205

Summary of Issues Discussed at the
First Meeting of the Task Force on Genetic Testing
April 13-14. 1995 - Baltimore. MD

I.     Definition of Genetic Tests. The definition is critical to the scope
of the Task Force's work and its recommendations. For now, the Task Force is
 using the following broad definition: The analysis of human DNA,

chromosomes, proteins or other gene products to detect disease-related
genotypes, mutations, phenotypes, or karyotypes for clinical purposes. Such
purposes include prediction of disease risks, idernificanon of carriers,
monitoring, diagnosis or prognosis, but not do not include tests conducted
purely for research. The Task Force has not decided whether acquired as well
 as inherited mutations fall in its purview.

II.     Issues in Genetic Test Development.

     A.     Scientific Validation:  Of prime concern to the Task Force is
validation of genetic tests. Determining how good a test will be in terms of
 sensitivity, specificity and predictive value will often require tracking

large numbers of people, perhaps for many years. There is often no "gold
standard" by which to measure these tests. Validity may differ between
high-risk groups and the general population. As a result, manufacturers and
the FDA face a significant challenge in assessing the efficacy of many
genetic test kits. Through the creation of a Subcommittee on Scientific
Validation the Task Force immediately set out to develop validation
criteria. Ensuing approaches to meet those criteria include: guidelines
developed by the biotechnology industry and/or professional genetics
organizations, and FDA regulation. Granting manufacturers provisional
pre-market approval so they could market test kits and receive fair return
while continuing to collect validation data will also be considered.

     B.     Institutional Review Boards (IRBs). Whenever a device (which
includes probes, primers and other key test reagents) that has not been
previously approved is used to make a clinical decision or to provide a
patient with information, the FDA requires submission of a research protocol
 to an IRB for approval. Absence of a confirmatory test, as is often the
in genetic testing, requires the laboratory or manufacturer to obtain an
investigational Device Exemption from FDA. FDA has not enforced these
requirements and the survey of companies and laboratories conducted for the
Task Force suggests that they are not always complied with.

     C.     Home Brews. Home brews are probes, primers or other reagents
made by laboratories for internal use in the development or provision of
testing services. Because such brews are never marketed, they elude review
by the FDA. Consequently, the safety and efficacy of the tests developed
with home brews are not formally established. CLIA has some potential to
regulate the clinical use of home brews through its lab quality standards.
HCFA and FDA have discussed the problem but not collaborated to resolve it.

     D.     Off-Label Use. Off-label use of genetic tests occurs when a test
 kit or other medical device approved by the FDA for one purpose is used in

developing and performing tests for other uses. An example is the use of
maternal AFP kits, cleared for detecting neural tube defects, in testing for
 Down Syndrome. The Task Force noted that while manufacturers can only
a device's intended use, clinical laboratories use the tests for other,
unapproved applications. Off-label use could grow as more test kits obtain
clearance. The Task Force noted the Institute of Medicine's recommendation
that the FDA require identification of all possible uses of tests. So far,
the FDA has not pursued that course.

     E.     FDA In-Vitro Device Regulations. The FDA is in the process of
revamping its 510K "substantial equivalence" and pre-market approval (PMA)
criteria in order to streamline the approval process. Manufacturers may be
dissuaded from investing in development of test kits because of the time and
 cost of collecting the required validation data. The regulations are

hard-pressed to deal with certain tests, such as that for BRCAl, which can
take years to validate. The current regulatory scheme also has shortcomings
in dealing with home-brews and off-label use of genetic test kits. While
maintaining high standards for clearance of test kits, the FDA is challenged
 by a relative lack of resources in the face of a potential increase in


III.     Issues in Providing Genetic Tests.

     A.     Laboratory Ouality. The Clinical Laboratory Improvement
Amendments of 1988 (CLIA) regulate the quality of labs performing tests for
clinical use. The Act mandates minimum standards in quality control,
personnel, and proficiency testing. However, genetic tests are largely
unaddressed by CLIA. Aside from the limited "clinical cytogenetics"
subspecialty, there is no direct provision for ensuring the quality of
genetic test services and no proficiency testing.

     CLIA provides for the authorization or "deeming" of professional
organizations to serve as aecrediting entities in specialized testing areas,
 in lieu of CLIA requirements. To date, only the College of American

Pathologists (CAP) has been authorized by HCFA to accredit genetics testing
labs and oversee proficiency testing programs. Participation in the CAP
programs is voluntary. CAP and the American College of Medical Genetics are
helping train genetics lab inspectors.

     CLIA exempts labs licensed under state laws considered eq or more
stringent" than CLIA. Some states, such as New York, impose test regulations
 in areas CLIA leaves unaddressed. Having many different state regulations

increases the cost of compliance to the biotechnology industry. To address
these issues, the Task Force will consider the advisability of a genetics
specialty under CLIA. Having such a specialty may result in more consistent
federal standards.

     CLIA requires that labs performing clinical tests register with HCFA.
However, without such registration, HCFA is largely unable to identify labs
failing to comply with CLIA mandates. From the survey conducted for the Task
 Force, there is evidence that some labs performing genetic tests fail to

register with HCFA.

     B.     Informed Consent. The Task Force heard a variety of opinions
regarding informed consent for genetic testing. Some members felt the
potential effects of positive results, such as stigmatization and
discriniination, warranted informed consent for any genetic test. Another
view held that while informed consent was necessary, it need not require
formal documentation and could be obtained through conversation between a
physician and patient. Another member felt that routine genetic testing
should not require informed consent, which was more appropriate for research
 protocols than clinical services. Circumstances involving emergency

situations, in which informed consent for testing is impractical, and
pathological biopsies, in which analysis could reveal genetic disorders,
further complicated the issue. The Task Force will address the question in
its Subcommittee on Education, Counseling and Delivery of Genetic Tests.

     C.     Education. Counseling and Delivery. Properly educating consumers
 who are being offered or who receive genetic tests is a concern of the Task

Force. This entails fmding ways to indicate the limitations of current
technology, including predictive capabilities of tests. Several Task Force
members expressed the view that consumers should participate in formulation
of policies on test validation, access, delivery and follow-up.

     A common theme was that interpretation of test results and counseling
about their implications are integral parts of the test itself. Great care
must be taken in offering tests and communicating test results, especially
when there is no intervention of proven efficacy for an identified genetic
condition and little or no data on the impact of test results on people
being tested. Furthermore, the predictive value of these tests can vary
greatly and must be taken into account. Some interpretative services might
be provided by laboratories, but may prove costly, intrude on the practice
of medicine, and raise liability issues. The Task Force will consider the
extent of manufacturer and laboratory responsibility in assuring appropriate
 test education and post-test interpretation.

     Given the increasing likelihood that primary care providers will be
ordering genetic tests to aid in preventive care, their education in the
essentials of this technology is important.  Task Force members differed
over the extent to which primary caregivers could master the subject. Even
if sufficiently educated in genetics, the traditional directiveness of
primary care providers in advising patients may be less desirable than the
relative impartiality of genetic counselors. Nevertheless, some patients may
 expect and desire direction in this area. Genetic counselors could assume

the responsibility of properly interpreting test results, but there is a
shortage of counselors and training programs. For some tests, such as
TaySachs, providers are less involved; results are often sent to patients

     D.     Insurance and Reimbursement.  Insurers play a critical role in
determining the diffusion of genetic tests in the American health care
system by whether or not they will reimburse for them in pilot phases as
well as after they are marketed. Insurers look to FDA approval or indicators
 of general acceptance by the medical community, such as recommendations in

the literature or by professional groups. Cost-benefit or effectiveness
calculations of tests is also considered.

     The insurance industry is interested in the ability of genetic tests to
 reveal risk of future disease. At present, insurers are not requesting

genetic screening of potential insureds due to the cost and uncertain
predictive value of most genetic tests. Moreover, such underwriting
practices are not applicable to group coverage when they involve rare
diseases, except for small groups. However, insurers are interested in
learning who has been tested. They could then charge higher premiums to
those with identified genetic conditions, which could preclude their
purchase of coverage, or deny them coverage altogether. Issues of insurance
discrimination have been considered by another ELSI Task Force.

IV.     Orphan Diseases. Orphan diseases are rare genetic disorders for
which manufacturers have little incentive to develop test kits.
Consequently, research laboratories and academic centers often create their
own tests for these disorders. The Task Force noted that home brews
facilitate orphan disease testing. At the same time it recognized that such
tests might never be properly validated. Establishing collaborative
arrangements and adhering to FDA's investigational use requirements might
assure adequate development of orphan disease technology and validation. One
 drawback to commercial development is that with investigational use no

profit-making is permitted.

     Because testing for orphan diseases is infrequent, labs performing them
 only periodically may lack appropriate quality control. The Task Force

considered regionalization of orphan disease testing laboratories, to
promote the necessary expertise and reduce costs. New York State provides an
 Orphan Disease Exemption system that enables labs to simply state their

compliance with quality control regulations, subject to routine
verification. While compliance with CLIA requirements is not onerous on its
face, many smaller labs cannot meet the specified standards for tests
performed infrequently. Certificate fees are scaled to the volume of

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