![](media/image1.png){width="1.2222222222222223in"
height="0.9618055555555556in"}

December 6, 2005

Andrew C. von Eschenbach, M.D.

Acting Commissioner of Food and Drugs

U. S. Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857-0001

**\[Docket No. 2001D-0044\]**

**Draft Guidance for Industry and Food and Drug Administration Staff:
Recommendations for Clinical Laboratory Improvement Amendments of 1988
Waiver Applications; Availability**

Dear Dr. von Eschenbach:

On behalf of the American Association of Bioanalysts ("AAB"), we
appreciate the opportunity to submit written comments on the Food and
Drug Administration's ("FDA") Recommendations for Clinical Laboratory
Improvement Amendments ("CLIA") of 1988 Waiver Applications (hereinafter
referred to as "draft guidance").

AAB represents the owners, directors, supervisors, and technologists of
community clinical laboratories. As laboratory professionals, the
quality and accuracy of laboratory testing are our top priority, and
that is why the high incidence of laboratory errors that occur in waived
testing sites seriously concerns us.

This draft guidance is based on the FDA's interpretation of CLIA, an
interpretation that continues to concern AAB, particularly in the
definitions and factors that the FDA uses to determine what a "waived"
test is. In particular, AAB fears that the FDA's interpretation of a
"waived test" under CLIA, as evidenced by this and previous draft
guidances, continues to present a threat to the patient public's safety
and health.

# Comments on Elements of the Draft Guidance

Since the draft guidance is an extension of the proposed regulations of
1995 and the document of March 1, 2001, to which we responded with
comments (please see attachment to this comment letter), we are limiting
our current comments to the following additional concerns:

-   The statutory intent and definition of \"waived test\" as a basis
    for the conclusions of the draft guidance;

-   The continued reference to the 1995 regulatory proposal without
    nullification of its defects that fail to provide a more restrictive
    consideration of the waived test category;

-   The relationship of the waived test category to other levels of test
    categories and the need for greater restriction on the former;

-   The potential adverse effect of the waived test definition as
    indicated and the use of products derived therefrom on public
    health;

-   Public health and safety; and the

-   Differentiation between FDA tests approved for over-the-counter sale
    and waived tests.

In order to accurately appreciate the purpose of the inclusion of waived
tests and to understand the intent of that specific section of the law,
it is necessary to review the history of the legislation. The original
CLIA Act of 1967 was considered too limited and not sufficiently
inclusive of all clinical laboratories. Laboratory errors subsequently
occurred due to the lack of full inclusion. The 1988 Amendments to the
Act were site neutral and inclusive of any laboratory conducting tests
on materials from the human body for assessment of disease. The obvious
intent was to place all laboratory testing into regulated laboratories
with only minor exceptions.

A close examination of the history of the 1988 legislation does not
suggest an intent to separate any significant amount of testing from
regulations as applied to clinical laboratories. In seeking a prototype,
Congress turned to the few states that had comprehensive clinical
laboratory legislation. Hearings were held in both the House and Senate
with experienced state personnel testifying. At that time, there was a
state regulation that permitted the use of qualitative testing of
limited types, and this prototype was considered as suitable for
inclusion in the Act. The specific list of tests is included in the
initial 1992 regulations, and these clearly define the legal meaning of
"simple," as well as the requirement that regardless of result, there
will not be an adverse medical effect. The intent in both the state laws
of origin and the Federal Act are identical in that waived tests are
"simple" in operation and do not include automated or electronic systems
or other instrumentality.

Since the overall intent of the Act is to regulate equally all
laboratory facilities, personnel, and testing operations and controls,
we believe that the FDA has misinterpreted the law, misstated its
purpose, and incorrectly defined \"waived." There is clear evidence to
suggest that the draft guidance incorrectly expands the waived concept
beyond truly simple, manual processes, permitting operation and control
by those other than experienced and educated laboratory professionals,
in violation of the original purpose of the CLIA legislation.

*Definition of "Simple"*

The draft guidance attempts to define "simple" with the criteria in
Section II. "Simple" in the statute certainly does not mean that a
self-contained, electronically complex process is \"simple\" by
definition, even though only a drop of blood is added. It should be
noted that such complex processes and equipment are common in well
managed and supervised laboratories, and that these processes and
equipment frequently need attention and repair by well-trained
laboratory personnel. Such equipment may only involve adding a drop of
material to a complex system, but elements of proficiency and quality
control require expert supervision. Moreover, the original purpose of
clinical laboratory quality legislation at both state and federal levels
was to assure that all laboratory testing is performed and under the
control of trained clinical laboratory personnel.

The statement in the 1995 proposal, which is reiterated in the draft
guidance, that quick reference instruction sheets be written at no
higher than a 7^th^ grade reading level presents a potentially serious
threat to patient safety and health. We are confident that the majority
of patients would object to this low standard for the processing of
their tests. In addition, the characteristics of tests described in the
draft guidance indicate that their complexity and understanding require
instructions that may need to be written at a level well beyond the
7^th^ grade in order for the tests to be conducted properly and without
error.

*Definition of "Insignificant Risk"*

The draft guidance misinterprets the meaning of "insignificant risk."
The reference to waived tests needing to be "more robust" than
non-waived tests skirts the real issue, which is that very few, if any,
laboratory tests worth performing have an "insignificant risk of an
erroneous result."

Even tests that were automatically waived in the 1992 CLIA regulations,
or which have been approved for over-the-counter (OTC) sales, have a
significant risk of an erroneous result. According to former HCFA
administrator Gail Wilenksy, Ph.D.:

"Although a test in which glucose is measured by a meter may be a simple
procedure to perform accurately, an incorrect test result could pose a
reasonable risk of harm to a patient..." (New England Journal of
Medicine, Vol. 234, No. 9, February 28, 1991, p. 636)."

Problems with "waived" blood glucose meters continue to be encountered,
from the 1991 deaths of several diabetic patients at Maryland's Seton
Hill Manor nursing home, to mass recalls of a number of blood glucose
meters, to recent Alerts issued by the FDA's office of In Vitro
Diagnostic Device Evaluation and Safety, which

"recently received a report of a patient who suffered irreversible brain
damage following an aggressive insulin treatment that was given for
elevated glucose readings. Unfortunately, the elevated glucose readings
were incorrect because the glucose monitoring device, which was unable
to distinguish between glucose and maltose, was reacting to the maltose
in the intravenous immunoglobulin solution that the patient was
receiving." (November 9, 2005)

On October 26, 2005, the FDA notified health care providers and patients
of a problem with another company's blood glucose meters. The meters can
be switched unintentionally from one unit of measurement to another,
resulting in an inaccurate blood glucose interpretation by the reader,
which could lead to an improper patient dosage of insulin. The patient
then could develop hyperglycemia, which is a serious and sometimes
life-threatening condition.

Moreover, [Consumer Reports]{.underline} reported in August 2005 that
although most of the blood glucose monitors they tested were reasonably
accurate, the readings varied in consistency, which [Consumer
Reports]{.underline} says is more important than accuracy.

In addition, the confusion resulting from the description of
"insufficient risk of an erroneous result" as part of insignificant risk
as applied to "waived" tests becomes most important in the area of
infectious disease. In this case, a definitive result is nearly
diagnostic. Also, it is an area in which the issue of erroneous results
is immediately detrimental to the patient. Assume, for example, that an
HIV test is included in the waived category. In this case, there may be
multiple causes that affect the proper operation of this test kit as
well as variability among patients. If the result is a false positive or
false negative, there will definitely be an adverse effect on the
patient. And if a test for Streptococcus agalactiae is falsely negative,
is there no adverse effect on the newborn? In short, AAB believes that
it is an incorrect interpretation of the statute to assume that a waived
test in the hands of persons not trained in laboratory science is
acceptable, given that the statute provides for the public benefit of
well trained persons for all clinical laboratory examinations.

Finally, we note that the determination of a method posing unreasonable
risk of harm to the patient if performed incorrectly should not only be
made by the Secretary, but also with the advice of a board of qualified
practitioners.

*"Hazard" Factors*

Although controls can be suggested, there is no way to prevent the
potential hazards from use in the uncontrolled sites of use in the
marketplace.

*Fail-Safe and Failure Alert Mechanisms*

These concepts are interesting but only on very theoretical grounds. It
seems doubtful that these non-regulatory \"suggestions\" will receive
serious attention by manufacturers.

*"Waived" Tests and Public Health*

There is significant concern among public health workers about the
effect of waived tests for screening of infectious disease. Consider the
use of a waived test by a person with a 7^th^ grade reading level for
the determination of a causative agent of a communicable disease that
can cause an epidemic. Certainly no public health official would rely on
such a test used by such personnel for determining control procedures.
Yet, this information from one source compared to data derived from
moderate or high complex testing facilities could result in significant
confusion and increase costs.

We also question whether the FDA may be abdicating its responsibility
for assuring that safety is a primary consideration for *all* devices,
not just certain categories of them. In the field of

laboratory devices and methods, the maximum in safety assurance is
achieved when all testing is performed in qualified laboratories. (Some
exceptions are recognized when health screening is performed by trained
laboratory personnel, since such procedures are not used for final
evaluation of patient health.)

In spite of the proposed complex procedures for developing waived tests,
the two elements necessary for safety in patient testing are missing: 1)
competent laboratory personnel, and 2) control and regulation based upon
the complexity of the process inherent in the test procedure. **There is
no doubt that if the lack of adequate regulation by FDA continues,
potential errors of public health significance will occur.**

The draft guidance states that "simple" precludes any test in which
results must be reported to a public health department. Therefore, it
must be concluded that no waived test can be applied to infectious
disease, such as screening for HIV, Lyme disease, Streptococcus, or
other infectious diseases. We are concerned, however, that some tests
for such purposes may be approved by the FDA, due in part to pressure
from manufacturers. In the 1995 proposed regulations for waived testing,
the agency stated that, "...manufacturers and producers ultimately will
benefit in the form of increased sales and distribution of tests
categorized as waived." Despite this recognition by the FDA, we
sincerely hope that the agency will focus first and foremost on the
potential detriment to public health and safety inherent in waived
tests.

*\
Differentiation between FDA tests approved for over-the-counter (OTC)
sale and waived tests*

The interpretation and assumption based on this part of the statute
requires some clarification. It does not mean that OTC tests are the
same as waived tests. There is a dichotomy of interpretation that must
be considered.

It is clear that the OTC test does not have to meet the requirements of
non-waived laboratory tests. However, it also must be assumed that OTC
tests are intended for use by the purchaser as a means of self-test for
his or her medical problem, such as glucose testing for diabetes. There
is no implication, however, that such tests can be used by the purchaser
to test others. In other words, no such test can be applied as a waived
test for screening patients unless it is separately and individually
defined for this purpose. The responsibility and liability relevant to
an OTC test applies to the purchaser, as it is to only be used upon him
or her.

The waived test, on the other hand, is made for sale in the marketplace
for use by those in "Certificate of Waiver" laboratories who apply the
tests to others for medical diagnostic purposes. The relationship is not
between manufacturer and patient, as in OTC tests, but rather between
the manufacturer and the "Certificate of Waiver" laboratory.

This guidance specifically points out that it does not address test
systems cleared or approved by the FDA for over-the-counter or
prescription home use, "since these automatically qualify for CLIA
waiver \[42 USC 263a(b)(3).\]"

The implication made here is that the FDA's hands are tied when it comes
to establishing the criteria for waiving tests approved for
over-the-counter use. But that is not true. The FDA has **full** control
over these criteria, but chooses to maintain two sets of criteria for
waiving tests: One for approving OTC tests and one for other tests as
described in this draft guidance.

This bifurcated system is unnecessary and not in the best interest of
the patient public. This guidance, if it has any merit at all, should be
applied to **all** applications for waiver, including those applying for
over-the-counter approval.

**Summary of Specific Recommendations**

1\. Return to the original intent of CLIA and its amendments by bringing
all laboratory testing activity into an environment of control,
standardization, and operation by skilled and experienced medical
laboratory personnel. Recognize that the waived category was intended as
a limited classification for a few, simple, manual tests for qualitative
purposes only;

2\. Return the large majority of waived tests to their proper complexity
category;

3\. Assure that the performance of all tests, including waived tests,
are documented and recorded;

4\. Provide evidence that all decisions regarding waived testing have
been referred to appropriate personnel at the Centers for Disease
Control and Prevention ("CDC") and the Clinical Laboratory Improvement
Advisory Committee ("CLIAC") for opinion and discussion;

5\. Provide labels on all waived tests that indicate in large type that
the results of the test do not establish a diagnosis of a specific
disease. Only a physician can make the diagnosis;

6\. Establish a separate advisory committee consisting of a board of
qualified, non- government participants that will review and approve any
test procedure brought forward under the classification of "waived."
This includes the various factors regarding approval of each analyte;

7\. While the draft guidance now provides greater detail as to what
manufacturers should do, there are no defined criteria to be used by the
FDA in judging whether a method is acceptable. In order to make the
approval process more objective, there should be a subdocument defining
allowable error, precision, etc., which differs for each analyte. These
elements should be outlined in a publicly available document so that
there is no doubt as to a method\'s acceptability or failure.

As a professional association that cares deeply about the quality and
accuracy of laboratory testing, AAB welcomes the opportunity to comment
on your agency's guidance. We look forward to hearing your responses and
we are willing to discuss these issues with you in greater detail.

Sincerely yours,

![](media/image2.png){width="1.9951388888888888in"
height="0.6958333333333333in"}

Mark S. Birenbaum, Ph.D.

Administrator

Attachment: AAB's Comments on the 2001 Draft Guidance