Clinial Laboratory Improvement Advisory Committee (CLIAC)
Meeting Summary - August, 1995
Summary Report
August 30-31, 1995
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Clinical Laboratory Improvement Advisory Committee
August 30-31, 1995
Summary
Table of Contents
I. Record of Attendance
II. Welcome and Announcements
III. Topics
CLIA Update/Centers for Disease Control and Prevention (CDC)
CLIA Update/Health Care Financing Administration (HCFA) Survey
Data
CLIA Update/Food and Drug Administration (FDA)
Quality Control Requirements/Framework for the Final Regulations
Public Presentations on Quality Control
Report on Subcommittee on Proficiency Testing, Quality Assurance
and Quality Control
Quality Control Limits
IV. Public Comments
V. Concluding Remarks
VI. The Addenda
Record of Attendance
The Clinical Laboratory Improvement Advisory Committee (CLIAC) met at the
Swiss'tel, 3391 Peachtree Street, in Atlanta, Georgia, on August 30-31, 1995.
Those in attendance are listed below:
Committee Members Ex Officio Members
Dr. J. Scott Abercrombie Dr. Carlyn Collins, CDC
Dr. Paul Bachner Dr. Steve Gutman, FDA
Dr. Regina Benjamin Ms. Judith Yost, HCFA
Ms. Michelle Best
Ms. Virginia Charles
Dr. Susanne Gollin
Dr. Stanley Inhorn Executive Secretary
Dr. Verlin Janzen Dr. Edward Baker
Dr. J. Stephen Kroger
Dr. Aliza Lifshitz
Dr. Bereneice Madison
Dr. Wendell O'Neal Liaison Representatives
Ms. Deborah Reed Dr. Fred Lasky (HIMA)
Dr. Patricia Saigo
Dr. Morton Schwartz
Mr. Elliott Segal
Centers for Disease Control and Prevention
Ms. Nancy Anderson
Dr. John Astles
Ms. Rosemary Bakes-Martin
Ms. Louise Barden
Ms. Carol Bigelow
Dr. Joe Boone
Ms. Sheila Boring
Ms. Gail Bosley
Ms. Diane Bosse
Ms. Genoria Bridgeman
Ms. Cheryl Coble
Ms. Debbie Coker
Ms. Crystal Frazier
Ms. MariBeth Gagnon
Ms. Sharon Granade
Mr. Tom Hearn
Mr. Edwin Holmes
Dr. Adam Manasterski
Dr. John C. Ridderhof
Ms. Eunice Rosner
Mr. Darshan Singh
Ms. Elva Smith
Mr. Gregory Smothers
Dr. Tina Stull
Ms. Julie Wasil
Ms. Glennis Westbrook
Ms. Rhonda Whalen
Clinical Laboratory Improvement Advisory Committee
The Secretary of Health and Human Services is authorized under Section
353 of the Public Health Service Act, as amended, to establish standards to
assure consistent, accurate, and reliable test results by all clinical
laboratories in the United States. The Secretary is authorized under Section
222 to establish advisory committees.
The Clinical Laboratory Improvement Advisory Committee (CLIAC) was
chartered in February 1992 to provide scientific and technical advice and
guidance to the Secretary and the Assistant Secretary for Health regarding
the need for, and the nature of, revisions to the standards under which
clinical laboratories are regulated; the impact on medical and laboratory
practice of proposed revisions to the standards; and the modification of the
standards to accommodate technological advances.
The Committee consists of 20 members, including the Chair. Members are
selected by the Secretary from authorities knowledgeable in the fields of
microbiology, immunology, chemistry, hematology, pathology, and
representatives of medical technology, public health, clinical practice, and
consumers. In addition, CLIAC includes three ex officio members, or
designees: the Director, Centers for Disease Control and Prevention; the
Commissioner, Food and Drug Administration; the Administrator, Health
Care Financing Administration; and such additional officers of the U.S.
Government that the Secretary deems are necessary for the Committee to
effectively carry out its functions. CLIAC will also include a non-voting
liaison representative who is a member of the Health Industry
Manufacturers Association and such other non-voting liaison representatives
that the Secretary deems are necessary for the Committee to effectively carry
out its functions.
Due to the diversity of its membership, CLIAC is at times divided in the
guidance and advice it offers to the Secretary. Even when all CLIAC
members agree on a specific recommendation, the Secretary may not follow
their advice due to other overriding concerns. Thus, while some of the
actions recommended by CLIAC may eventually result in changes to the law,
the reader should not infer that all of the advisory committee's
recommendations will be automatically accepted and acted upon by the
Secretary.
Welcome and Announcements
The meeting was called to order by CLIAC Chairman Dr. Morton Schwartz.
Dr. Edward Baker, Director of the Public Health Practice Program Office, CDC, and
Executive Secretary of the CLIAC welcomed the committee members. Dr. Schwartz
stated the role and function of CLIAC. Mr. Kevin Malone, Attorney Advisor, CDC,
reviewed the conflict of interest forms and format for financial disclosure
statements to be made at each CLIAC meeting. The committee members then made
self-introductions and disclosure statements of their relevant financial interests as
they relate to any topics to be discussed during the CLIAC meeting.
Presentations and Committee Discussion
CLIA Update/CDC
Dr. Carlyn Collins, Director of the Division of Laboratory Systems, CDC, stated
that the waived and accurate and precise technology (APT) proposed rules are still
under review, but noted that Vice President Gore indicated at a press conference
that these rules would be published in the fall. [The proposed rule clarifying the
waived criteria was published on September 13, 1995, and the proposed rule to
create the APT subcategory was published on September 15, 1995.]
CDC has received applications for waiver of 13 test systems, including 33 analytes.
Two test systems have been approved for waiver and the review of the other
applications is ongoing.
CDC will host a laboratory institute entitled "Frontiers in Laboratory Practice
Research" on October 1-3, 1995 in Atlanta.
CLIA Update/HCFA Addendum A
Ms. Judith Yost, HCFA, presented a status report on CLIA implementation and a
summary of the types of deficiencies cited in the first and the second cycle
inspections. She noted that approximately 10% of the second cycle inspections have
been completed and that condition level deficiencies have decreased from 14% (first
cycle) to 9% (second cycle). She attributed the improvement in laboratory
compliance to the educational aspects of the inspection process.
Committee Discussion
One committee member asked about the denominators (total number of laboratories
inspected) for the percent of laboratories with condition level deficiencies in the first
and second cycle inspections. Ms. Yost stated that the denominators were
essentially the same. In addition, she noted some changes in types of certificates
due to the recent expansion of personnel (mid-level practitioners) allowed to
perform provider-performed microscopy procedures.
CLIA Update/FDA Addendum B
Comparison of CDC Review for Waiver and FDA Clearance for Over the
Counter (OTC) Products
In response to a previous request from CLIAC, Dr. Steve Gutman, FDA, presented a
comparison of the FDA review process for clearance of OTC (home use) products
and the CDC review process for determining waiver. While the processes are quite
similar with respect to labeling and data requirements, he noted that it would be
very difficult to harmonize the technical requirements, and somewhat difficult to
harmonize the informational requirements. The two agencies operate under
different statutes, serve slightly different constituencies, and have regulatory
requirements which are parallel but not identical. Although some progress has
been made in harmonizing the requirements, Dr. Gutman stated that there
continue to be statutory differences in the charges to the two agencies.
Committee Discussion
One committee member asked why the FDA cannot accept a submission that meets
the CDC guidelines for waiver approval. Dr. Gutman stated that the FDA can
accept a submission based on the guidelines for waiver but that the FDA cannot
require that type of submission. The committee member noted that since the CLIA
law requires waiver approval (if application for waiver is made) of all devices
cleared for home use by the FDA, it would seem reasonable for the FDA to consult
with the CDC to determine whether the FDA could clear for home use any test
system waived under CLIA by the CDC. Dr. Gutman indicated that this would not
be possible due to FDA's workload and limited resources.
Status of FDA Approval of Cytology Instruments
External consultant review panels have recommended FDA approval of two
instruments designed to assist laboratories in improving or enhancing the quality
control (QC) procedures associated with PAP smear examinations.
The Papnet provides an adjunct test to the laboratory's routine examination of
slides and rescreen of 10% of negative cases, which includes random rescreen and
high risk cases. Following the initial manual screen of all slides by
cytotechnologists and the mandatory rescreening of 10% of the negative cases, all
negative slides are sent for review by Papnet, an automated computerized system
which identifies by video the most suspicious 64 cells and 64 clusters of cells. The
video and slides are then returned to the laboratory for cytotechnologist review to
determine which of these slides should be rescreened.
The AutoPap instrument is intended for use as an alternative to the random
rescreen QC procedure. Laboratories would continue to have cytology personnel
perform the primary manual screen of all slides, but, in lieu of the random rescreen,
the instrument, through computer algorithms, would select a 10% (or higher
percent) subpopulation of negative slides which are more likely to be positive. The
laboratory would still be responsible for review of high risk cases.
Both instruments were designed to reduce the false negative rate of Pap smears,
but each instrument has different claims or functions supported by different
research studies. The FDA expects timely approval of both instruments, and
Dr. Gutman noted that PAP smear CLIA QC requirements may need to be reviewed
for applicability to these and future systems.
Committee Discussion
Several members commented on the use of these systems. Some committee
members expressed concerns about delays in reporting results and the increased
cost, but Dr. Gutman responded that the FDA does not consider cost effectiveness or
compare the systems to one another. Another committee member was concerned
about the potential for "off-label" use of the instruments. Dr. Gutman said that the
products must have specific labeling that indicates the instruments are not to be
used as primary screening devices. Another member was concerned about publicity
or media control. She said that, due to media coverage, the public's concept is that
false negative results are due to errors in reading PAP smears, when in fact many
errors are due to inadequate specimen collection. Dr. Gutman stated that the FDA
has clear authority to regulate promotion and advertising, but not television
specials. Another member wanted to know the time frame for approval by the FDA.
Dr. Gutman anticipated that, although plant inspections need to be performed,
approval will occur in the next fiscal year. [AutoPap received FDA approval on
September 29, 1995; Papnet was approved on November 8, 1995.] Another member
asked if the data presented to the FDA is available to the public. Dr. Gutman
replied that a transcript of the proceedings can be purchased.
QC Requirements/Framework for the Final Regulations Addendum C
Ms. Rhonda Whalen of the CDC set the stage for the Committee's deliberations on
the framework, format and content of the final regulations. First, she reviewed the
guiding principles of the CLIA regulations which are to assure quality testing,
specify minimum standards, assure physician and patient access to testing and
accommodate new technology. The most challenging task in developing regulations
is accommodating emerging technology. Laboratory testing is constantly changing
and the regulations should not be a barrier to innovation.
Provisions of the CLIA law provided the basis of the 1992 regulations. Standards
were developed based on test complexity. The provisions in the law are broad and
not specific with regard to the content of the standards for personnel, proficiency
testing (PT) and QC. The CLIA regulations for personnel, PT and QC are
considered to be interrelated, with quality monitoring activities incorporated into
the quality assurance (QA) requirements.
In developing the 1992 CLIA regulations, experience with previous regulations and
inspections was considered. In addition, the regulations incorporated input from
the 50,000 comment letters and consultation received during the CLIA rule making.
In the CLIA regulations, QC is defined as the processes necessary to prevent and
detect laboratory errors, and the function of QC is to monitor the total testing
process, i.e. all the laboratory's activities in producing a test result, not just the
analytical phase (test performance). The total testing process includes the
environmental conditions involved in testing in the laboratory, as well as specimen
manipulation, processing and handling.
In the QC regulations, there is a phase-in period for certain requirements
applicable to unmodified, moderate complexity test systems cleared by the FDA
through the 510K or PMA process. For these systems, basic minimum
requirements were applicable for the first two years of regulation, which included
provisions for laboratories to follow manufacturers' test system instructions and, in
addition, perform some simple QC procedures. During this phase-in period,
previously unregulated laboratories would gain experience with QC procedures and
the FDA would develop the process for review of test system QC instructions for
CLIA compliance. At the end of the phase-in period, the QC requirements would be
the same for moderate complexity and high complexity testing. The phase-in,
which was to end September 1, 1994, was extended in December 1994 to
September 1, 1996 (59 FR 62606).
Ms. Whalen then compared the current QC requirements for moderate and high
complexity tests. She described the relatively simple, basic requirements for
laboratories performing unmodified, moderate complexity tests cleared by the FDA
510K or PMA process.
The next step in CLIA regulation development is to complete the rule making
process initiated in 1992. In developing revisions to the CLIA regulations, the basic
tenets (presented previously) used in developing the 1992 regulations would be
considered, as well as the following:
September 1, 1996 expiration of the QC phase-in for unmodified commercial,
moderate complexity test systems.
Comments to the February 28, 1992 regulations.
Experience with inspections, training, review of accreditation and state
program requirements, and public communication and correspondence. (For
example, in July 1995 CDC convened a meeting of QC consultants to address
many of the topics under discussion at this meeting.)
Regulatory reform mandate to ensure that regulations are simple,
understandable, cost effective and ensure quality, while imposing the least
amount of burden.
Ms. Whalen then presented the CDC approach for revising the QC section of the
CLIA regulations. The basic concept of monitoring the total testing process would
be maintained. Changes would be made to the regulatory framework to simplify
the structure and language of the regulation. A core set of requirements, which
applies to all test systems, and a mechanism to deal with exceptions and
alternatives would be established. In addition, improving the organization and
names of the subparts and eliminating redundant requirements, where possible,
would make the regulations more understandable. As an example, Ms. Whalen
noted that some parts of the testing process (specimen handling, processing and
manipulation) are included in the Patient Test Management subpart, which causes
confusion, since the same topics are addressed under the procedure manual
requirements in the Quality Control subpart. Also, some activities are
inappropriately included in the Quality Assurance subpart.
Committee Discussion
The Chairman asked how CLIAC could assist in regulations development.
Dr. Baker said that CLIAC could provide suggestions and examples of regulatory
approaches that have been effective, as well as ideas about how to reduce the
regulatory burden of the requirements. One committee member thought that the
concept of monitoring the total testing process has been lost due to the structure of
the regulation. She noted that the organization is confusing and said that QA is
really quality improvement. She said that the parts of the regulation should be
organized in a manner consistent with the testing sequence, beginning with the test
requisition and ending with reporting test results. Another member agreed with
this approach, but emphasized that the intent of the regulations should not be
changed if the structure and wording are changed. He felt that test complexity is
no longer an issue, but laboratories need to know what to do to comply with the
regulations. He encouraged efforts to simplify the regulations. One member noted
that most confusion about the regulations occurs in the low volume, moderate
complexity laboratories and suggested that a "tier approach" would make the
regulations more understandable. Similarly, another member commented that
although the regulations should be "site neutral," for ease of understanding, all
requirements for physicians' office laboratories (POLs) should be located in one
section of the regulations. Another member stated that laboratories having the
most difficulty understanding the regulations are the previously unregulated labs,
which may have untrained personnel. He felt that educating personnel on how to
comply with the regulations may be more important than changing the language in
the regulations.
One committee member said that making the regulations more understandable was
not the issue. He felt that CLIAC should challenge the rules instead of reworking
them; he favored having as few rules as possible. Another member asked whether
the regulations are working, and if the desired accuracy and reliability have been
achieved. He said that studies are needed to determine this. In his view, through
studies and data, it would be possible to determine which areas of the regulations
should be less stringent and which should be strengthened. The data could show
whether fewer or more controls are needed. There was some agreement that
definitive studies are needed to support a change to less stringent requirements,
and that it would be appropriate for manufacturers to financially support such
studies. However, one member disagreed that data were needed to support a
change to less stringent requirements. Another member commented that
compliance with the regulations, i.e. fewer citations in the second cycle of
inspections, does not necessarily correlate with laboratory improvement. The
HCFA representative, Ms. Yost, responded that the survey process has identified
some significant laboratory problems and that there appears to be a relationship
between improved quality in laboratories that have fewer citations in their second
cycle inspections. She also stated that PT data indicates improvement in laboratory
performance in PT over time. A committee member noted that PT measures a
process, not an outcome. Dr. Baker noted that CDC has research studies in
progress which measure outcomes. The Chairman suggested that a presentation of
data illustrating whether there has been improvement in laboratory performance
since CLIA implementation, would be a good topic for a laboratory institute or a
future CLIAC meeting.
Public Presentations on Quality Control
American Society for Microbiology (ASM) Addendum D
Dr. Alice Weissfeld presented data from a recent survey of microbiology
laboratories documenting the incidence of QC failures of some commercial reagents.
Based on the survey results, the ASM recommended decreasing the frequency of QC
testing for these reagents.
Committee Discussion
Two committee members agreed that the ASM survey is valuable in collecting data,
and such surveys could be used in areas other than microbiology. The chairman
asked if a 22% response rate was considered an acceptable rate of return.
Dr. Weissfeld said yes, based on information received from marketing people since
the survey was completed. She anticipated better returns on future surveys if
CLIAC supports this type of data collection. She also noted that, if CLIAC supports
the ASM recommendations to decrease the QC frequency of those reagents with low
failure rates, the ASM would be willing to expand the survey to include additional
reagents.
Dr. Baker commended the ASM on the data presented and asked the Committee for
feedback on the utility of the data and whether the CDC should consider the ASM's
recommendations for decreasing the QC frequency of these reagents. The
Committee supported the ASM recommendations and was in general agreement
that the regulations should be revised to reflect QC testing of microbiology reagents
in accordance with frequencies suggested by the ASM. The Chairman concluded
the discussion, stating that CLIAC encourages the ASM to conduct additional
surveys as planned.
Bayer Corporation Addendum E
Dr. Donald Parker reviewed the CLIA requirements related to the QC phase in for
commercial, moderate complexity test systems (cleared by the FDA through the
510(k) or PMA process) and noted that the FDA will not be able to review
manufacturers' QC instructions for CLIA compliance. Dr. Parker stated that the
Bayer Corporation believes that, if the FDA had been able to implement the CLIA
review process, QC procedures acceptable for FDA clearance would also be
acceptable under CLIA.
Dr. Parker explained that for some test systems, less frequent control testing is
appropriate. He stated that the FDA has cleared moderate complexity test systems
that have a QC frequency different from the CLIA requirements. In such cases,
Dr. Parker outlined the Bayer proposal to allow laboratories to meet the CLIA
requirements by following the manufacturers' QC instructions. Under the Bayer
proposal, those laboratories performing tests not cleared by the FDA would be
required to meet the current CLIA requirements (perform and document control
procedures using at least two levels of control materials each day of testing).
Dr. Parker stressed that today's technology supports the suggested change and
presented arguments for Bayer's position using the DCA 2000 system as an
example of alternative QC that should be acceptable under CLIA.
Committee Discussion
Committee members questioned how laboratories would know about test system
failures if QC checks were not performed. Dr. Parker responded that internal
checks are included in systems to notify operators of test system failures. Several
members were concerned about manufacturers determining the frequency of
laboratory QC testing. Dr. Parker noted that manufacturers have data to support
performance claims for testing QC at less frequent intervals than required under
the current regulations and, in his view, laboratories should be allowed to follow
manufacturer recommendations. One member expressed concern about relying
totally on the manufacturer, stating that many laboratories would not be able to
evaluate the manufacturer's data and make appropriate decisions regarding QC
frequency. The same committee member asked Dr. Gutman if the FDA reviews, or
will evaluate, the manufacturer's data supporting QC recommendations as part of
the FDA clearance process. Dr. Gutman stated that the FDA review process has
changed in the last few years, but the FDA does not review the manufacturer's data
for CLIA QC compliance. He also noted that the FDA lacks resources to review
manufacturers' data for QC compliance. He indicated that plant inspections by the
FDA may be more important than the premarket review process, as FDA has
observed that many failures occur when the manufacturer begins production. One
committee member noted that ultimately the reliability of instruments must be
determined by the user. Another member said he would not be comfortable with
relying on QC procedures recommended by the test system manufacturer, if the test
system was cleared by the FDA five to ten years ago.
Summarizing, the Chairman noted that the FDA does not have a process for review
of manufacturers' QC procedures for CLIA purposes and suggested that CDC might
consider the possibility of establishing some type of provision to allow alternative
QC procedures when supported by manufacturers' data. Dr. Collins stated that
reviewing QC procedures for each test system would be very labor-intensive and
require resources not currently available at the CDC. However, she pointed out
that many of the test systems might meet the requirements for the proposed APT
subcategory, and QC review would be part of the evaluation for APT categorization.
PT, QA AND QC Subcommittee Report Addendum F
Dr. Wendell O'Neal distributed and summarized the subcommittee report on the
two issues considered and presented the following recommendations of the
Subcommittee:
Requirements for test method verification
The regulations should be descriptive, but not proscriptive.
Requirements should be included in the regulations, but not protocols.
Prior to reporting results on patient specimens, laboratories should, at
a minimum, verify the accuracy, reproducibility and reportable range
of the test method.
Appropriate materials for QC testing
Maintain the current requirement that two controls be tested per run,
and that the regulations not specify the analyte levels in QC samples.
Committee Discussion on Method Verification
Dr. O'Neal noted the Subcommittee's concern about the definition of "accuracy" as it
applies to verifying the performance of a test method and pointed out that a
mechanism exists for including definitions in the regulations. A few CLIAC
members suggested deleting from the test system verification section, the
requirement to verify "(G) Any other performance characteristic required for test
system performance" (42 CFR 493.1213). One member felt that it should be
clarified that the verification requirements apply to the user, not the manufacturer.
One committee member was under the impression that the test system verification
requirements apply only to quantitative procedures. Another member thought that
sensitivity and specificity should be verified. The CLIAC Chairman clarified the
subcommittee recommendation that, in general, for moderate complexity test
systems, only accuracy, precision and reportable range, as stated on the
manufacturer's label, need to be verified. He also stated that reportable range
meant linear range as stated by the manufacturer. One committee member said
that there are ambiguities in the requirements for verifying accuracy, precision,
and reportable range and laboratories are receiving conflicting interpretations of
the requirements from HCFA, CDC, accreditation organizations and State agencies.
The Subcommittee's recommendation was intended to provide relief for the small
laboratory by specifying the minimal user performance verification required for new
test systems. The Chairman noted that CLIAC's recommendations are intended to
provide guidance to CDC on the requirements to include in the final regulations,
and emphasized that the Subcommittee does not recommend specifying in the
regulations "how to" comply with the requirements.
Dr. Collins noted that the regulations were written to allow maximum flexibility,
but that many labs, especially previously unregulated labs, want specific guidance
that would include verification protocols. The Committee acknowledged that
previously unregulated laboratories need assistance and was in support of
providing guidance to laboratories for determining appropriate protocols to verify
test method performance. In general, the Committee agreed that the regulations
should specify what is required, with one member suggesting that the regulations
include examples of protocols. Other members thought there should be a
mechanism external to the regulations, for providing suggested protocols for
verifying test systems. One member suggested including protocols in the HCFA
State Operations Manual, while other members felt that PT providers, professional
organizations or manufacturers should distribute guidelines or suggested
procedures for test system verification.
CLIAC Recommendation:
Accept the Subcommittee's recommendation to include in regulations the
descriptive requirements but not specific protocols for meeting the
requirements.
Prior to reporting patient results, the laboratory should, at a minimum,
verify the accuracy, reproducibility and reportable range of the test method.
Committee Discussion on QC Samples
Noting that the subcommittee members were not unanimous in the
recommendation to maintain the current requirement to test two QC samples per
analytical run, Dr. O'Neal agreed with another member's observation that probably
all five subcommittee members voted as they did for different reasons. He stated
that the Subcommittee's decision to maintain the current number of QC samples
was really a "default vote," i.e. the Subcommittee did not have a reason or basis to
justify a change. He noted that those who voted in favor of no change probably did
so because they could not suggest a more appropriate number of QC samples, and
were not in favor of deleting the requirement. He stated that perhaps a more
appropriate alternative would evolve from the CLIAC discussion.
The Chairman began the discussion by asking for a vote on whether CLIAC would
accept the Subcommittee's recommendation to maintain the number of QC samples
per run at two. The Committee voted against accepting the Subcommittee's
recommendation.
CLIAC members then discussed two alternative proposals to the subcommittee's
recommendation:
The regulations should not specify the number of QC samples required; QC
samples of appropriate number and frequency should be run to assure the
detection of laboratory errors. The laboratory director is responsible for
ensuring that appropriate QC is performed, and the laboratory must be able
to demonstrate the basis for testing less than [or more than] two QC samples
per run.
Regulations should require laboratories, at a minimum, to follow the
manufacturer's QC recommendations. The number of controls needed to
monitor test performance varies with circumstance and instrument, and the
manufacturer can best determine appropriate QC procedures for each device.
The laboratory director must be able to justify the reasons for not following
the manufacturer's QC instructions.
Discussion focused on whether the minimum number of QC samples per run should
continue to be two, or be changed to require more or fewer QC samples. One
member commented that QC activities cost money and that laboratories may be
reluctant to increase the cost per test by performing QC. He noted that
manufacturers have a financial incentive to reduce laboratory costs by eliminating
or reducing QC. Another member stated that the number of QC samples should not
be "zero." Dr. Collins reminded the Committee that CDC had only asked CLIAC for
input on whether the requirement to test two controls per analytical run, should be
changed. One member asked about the definition of a "run." Dr. Collins responded
that according to the regulations, a run cannot be greater than 24 hours. The
Chairman noted that in both proposals the laboratory director is responsible for the
QC policy. There was general agreement that the two proposals could be reworded
and combined as follows:
QC of appropriate number and frequency must be run to assure the
detection of laboratory errors.
One member wanted to add the phrase "in a timely manner," but the idea was
rejected due to the difficulty in defining timeliness. Another member wanted to
change the phrase "laboratory errors" to "analytical errors," but another member
thought that would imply monitoring only the analytical phase, not the total testing
process. One member pointed out that the purpose of running QC samples is to
evaluate patient results and determine whether the test values are correct.
Another member referring to a statement in the regulations, "control procedures are
performed on a routine basis to monitor the stability of a test system," noted that
performing QC may not ensure the detection of laboratory errors.
Ms. Yost expressed concern about making the requirement less stringent and less
specific when 35% of the laboratories surveyed by HCFA did not run two levels of
QC or follow the manufacturer's test system instructions. One member asked if
these laboratories had established QC policies. Ms. Yost responded that most of the
laboratories did not have policies, while some did not follow the established policies.
The discussion on the number of QC samples was tabled; it was suggested that
CDC consider the points discussed by the Committee and, at a future meeting,
present this issue along with supporting data reflecting the impact on
manufacturers, laboratories and the public.
In a brief discussion about specifying analyte levels in QC samples, the Committee
was in general agreement that producing this type of QC material would be
expensive and difficult, if not impossible.
CLIAC Recommendation:
Analyte levels for QC samples should not be specified in the regulations.
Quality Control Limits Addendum G
Dr. Joe Boone, of the CDC, in discussing the requirements pertaining to QC limits,
noted that although laboratories must assess test system accuracy and
reproducibility or precision, there is no requirement for a laboratory to document
the appropriateness of its QC limits. As determined during inspections, some
laboratories have no criteria for establishing appropriate QC limits. In which case,
the QC procedures of these laboratories may not be providing adequate patient
protection. Dr. Boone presented the following issues for CLIAC consideration:
Should laboratories be required to use acceptable protocols to document the
basis upon which the QC limits are established?
Should laboratories be required to periodically verify that their QC limits are
comparable to other laboratories that use comparable test methodologies?
Discussion on Establishment of QC Limits
Several members, in discussing the concepts presented, pointed out that
laboratories are currently required to document performance of the general QC
requirements and the laboratory director is responsible for ensuring appropriate
QC practices. One member was opposed to including in regulations, a definition of
acceptable QC limits. Another member noted that physician feedback was one way
to monitor the appropriateness of QC limits.
One member asked if the problem is philosophical or practical. Dr. Boone
responded that it is a practical problem, but that the extent of the problem is
unknown. He said that if a laboratory sets its limits so broadly that the QC values
are always within limits, performing QC would be pointless; conversely some
laboratories set their limits too narrowly. A member thought that the requirements
should not be increased unless there is data to support the change. Several
members were concerned about the phrase "using acceptable protocols." Dr. Boone
indicated that establishing QC limits on the basis of medical usefulness criteria
would be acceptable, but using PT performance criteria would not be appropriate.
CLIAC Recommendation:
Laboratories should be required to document the basis on which they
establish their QC limits. The phrase "use acceptable protocols" was not
included because such protocols would need to be defined.
Discussion on Verification of Comparability of QC Limits
The Chairman thought it would be very difficult for POLs to verify QC limits with
other laboratories. Another member agreed, stating that the databases don't exist
and questioned the benefit of such a requirement. He also questioned whether the
comparison should be based on methodology or clinical context. Dr. Boone said that
this would be a measure of the laboratory's reproducibility and that laboratories
needs to know if their reproducibility is not comparable to that of other laboratories
using the same device. Some differences in variability would be expected in
different clinical contexts. One member was concerned that this would shift the
laboratory efforts currently involved in ensuring accurate testing to focus on ensuring
comparability with another laboratory. Another member had concerns about which
laboratory should be used to verify comparability and questioned the burden and
value of determining comparability for each analyte.
Committee Recommendation:
Laboratories should not be required to periodically compare their QC limits
to those of other laboratories using comparable methodology.
Public Comments at End of CLIAC Meeting
1. Michael Zelin, Vice-President of I-STAT Corporation, addressed the issue of
developing regulations that are simple, yet flexible. He suggested that CDC look at
the structure of the FDA's Good Manufacturing Practices (GMP) regulations and
guidelines. The GMP defines the goals but not the "how to" for manufacturers. The
guidelines include examples of how manufacturers may comply with GMP.
2. See Addendum H for statement and letter to the Secretary of the Department
of Health and Human Services from the American Medical Technologists (AMT).
Ms. Linda Cromeans, President of AMT, noted that the minimum standards of most
certifying organizations exceed the CLIA personnel standards. The AMT feels that
the recognition of private-sector certifying organizations would streamline the
regulations without sacrificing testing quality. The American Association for
Clinical Chemistry and the American Society for Clinical Laboratory Scientists
have endorsed the AMT proposal and Ms. Cromeans stated that the AMT is
unaware of any opposition.
3. Mr. Robert J. Slomoff, representing HemoCue, referred to Dr. Gutman's
comparison of the FDA review process of OTC products and the CDC review process
for waived devices, and the problems with harmonizing the technical requirements.
He suggested that FDA, HCFA and CDC ask the Department's lawyers to review
the regulatory construction from a practical point of view and to determine the
types of devices approved for home use which might be granted waived status.
4. Richard Naples, Director of Regulatory and Government Affairs for
Boehringer Mannheim Corporation, stated that a colleague, David Phillips, has
submitted to the National Committee for Clinical Laboratory Standards (NCCLS) a
proposal for development of guidelines for alternative QC procedures. A group of
individuals met during the meeting of the American Association for Clinical
Chemistry in July and again at the Clinical Laboratory Management Association
meeting in August to discuss alternative QC. He said that CLIAC, CDC and HCFA
are dealing with similar issues and invited each agency to send a representative to
the group's next meeting in October.
The Chairman suggested that minutes of the group be sent to the CLIAC members.
[A copy of the minutes from the July 17, 1995 meeting was received after the
CLIAC meeting and is in Addendum I.]
Concluding Remarks
The Chairman presented certificates and letters of recognition to Dr. Stanley
Inhorn, Dr. Paul Bachner and Ms. Virginia Charles, retiring members of CLIAC.
The Chairman ended the meeting, but asked CLIAC members to remain for a group
picture.
I certify that this summary report of the August 30-31, 1995, meeting of the Clinical
Laboratory Improvement Advisory Committee is an accurate and correct
representation of the meeting.
/S/ Morton K. Schwartz, Ph.D.
Chairman
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