ESPECIFICACIONES CLIA

8/22/2019 ESPECIFICACIONES CLIA

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Has compliance with CLIA requirements really improved

quality in US clinical laboratories?

Sharon S. Ehrmeyera,*, Ronald H. Laessiga,b

aDepartments of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Room 6175,

1300 University Avenue, Madison, WI 53706 USAbPopulation Health Sciences, University of Wisconsin Medical School, Madison, WI 53706, USA

Received 18 December 2003; accepted 23 December 2003

Abstract

Background: The Clinical Laboratory Improvement Amendments of 1988 (CLIA88) mandate universal requirements for all

U.S. clinical laboratory-testing sites. The intent of CLIA88 is to ensure quality testing through a combination of minimum

quality practices that incorporate total quality management concepts. These regulations do not contain established, objective

indicators or measures to assess quality. However, there is an implicit assumption that compliance with traditionally accepted

good laboratory practicesfollowing manufacturers directions, routinely analysing quality control materials, applying quality

assurance principles, employing and assessing competent testing personnel, and participating in external quality assessment or

proficiency testing (PT)will result in improved test quality. Methods: The CLIA88 regulations do include PT performancestandards, which intentionally or unintentionally, define intra-laboratory performance. Passing PT has become a prime

motivation for improving laboratory performance; it can also be used as an objective indicator to assess whether compliance to

CLIA has improved intra-laboratory quality. Results: Data from 1994 through 2002 indicate that the percentage of laboratories

passing PT has increased. In addition to PT performance, subjective indicators of improved qualityfrequency of inspection

deficiencies, the number of government sanctions for non-compliance, and customer satisfactionwere evaluated.

Conclusions: The results from these subjective indicators are more difficult to interpret but also seem to show improved

quality in US clinical laboratories eleven years post-CLIA88.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Clinical Laboratory Improvement Amendments (CLIA88); Laboratory compliance; Quality laboratory results; Testing deficiencies;

Indicators of laboratory quality; Good laboratory practices

1. Introduction

To assess improvements resulting from the Clin-

ical Laboratory Improvement Amendments of 1988

and the most recent revisions in 2003, one must

first understand their underlying philosophy [13].

The CLIA88 regulations like the ISO 9000 docu-

ments codify, for all testing sites, a collection of

good laboratory practices associated with quality

laboratories [4]. By incorporating a total quality

management-based approach into the regulatory

process, the laboratory director is made responsible

for guaranteeing that appropriate quality practices

0009-8981/$ - see front matterD 2004 Elsevier B.V. All rights reserved.doi:10.1016/j.cccn.2003.12.033

* Corresponding author. Tel.: +1-608-262-0859; fax: +1-608-

262-9520.

E-mail address: [email protected] (S.S. Ehrmeyer).

www.elsevier.com/locate/clinchim

Clinica Chimica Acta 346 (2004) 3743


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are followed. CLIA88 specifically states that the

laboratory director must ensure that the . . . testing

systems. . .used. . .provide quality laboratory services

[covering] all aspects of test performance, whichincludes the pre-analytic, analytic, and post-analytic

phases of testing [2]. To achieve this goal, CLIA88

specifies a universal (applicable to all test sites) set

of minimum, good laboratory practices: (1) having

trained and competent testing personnel; (2) follow-

ing manufacturers procedural directions (calibration,

maintenance, etc.); (3) routinely performing and

evaluating daily quality control, responding to out-

of-control results and correcting problems; (4) ap-

plying total quality management and continuous

quality improvement principles and practices; (5)

participating in external quality assessments; (6)

and documenting all activities.

The only quantitative performance requirement in

CLIA88 is to successfully analyze three sets of PT

challenges per year. The mandated, minimum good

laboratory practices provide no absolute perfor-

mance standards. Instead, they take a quality manage-

ment approach requiring the director to implement

and set limits for the quality control parameters

appropriate for the intended use of the laboratory

results. To assess compliance with these practices,

CLIA88 requires that testing sites be inspected bi-annually. Test sites found out of compliance (either

with PT or inspection requirements) are subject to a

series of progressive sanctions ranging from requiring

plans of correction, to monetary fines, to testing

limitations, to revocation of the sites CLIA certifi-

cate, i.e., prohibiting testing entirely.

The regulation of US laboratories has a brief

history. From 1967 to 1988, 12,000 large clinical

and reference laboratories were required to follow

the quality standards embodied in two federal regu-

lations, the Clinical Laboratory Improvement Act of1967 (CLIA67) and Medicare 1968 [5,6]. The pur-

pose of these regulations was to improve the quality

of laboratory tests in federally funded programs and to

ensure that federal healthcare dollars were spent on

high quality laboratory tests. In the mid-1980s, a

series of newspaper articles highlighted laboratory

errors associated with Pap smear testing. The U.S.

congress generalized these errors and enacted the

CLIA88 amendments designed to ensure quality in

all laboratories including physicians offices. For the

first time, all clinical laboratory-testing sites were

required to meet uniform standards.

CLIA88 as implemented by the February 28, 1992

and subsequent regulations recognize three majorcategories of testing: waived, moderate complexity

and high complexity. Only laboratories registering as

moderate and high complexity are required to partic-

ipate in PT and to undergo bi-annual inspections for

the mandated, good laboratory practices. Waived tests

were originally limited to a total of nine analytes using

methodologies described as so simple to perform

that there is essentially no possibility of a wrong test

result or, if erroneous, pose no risk to the patient.

Most of these were already available, over-the-count-

er, without prescription to the general public.

2. Indicators of quality

Before determining whether the quality of test

results has improved as a result of compliance with

CLIA88, one must first attempt to do what CLIA

does notthat is to define quality and, to a lesser

degree, what level of quality is needed to meet good

laboratory practice standards. While adherence to

government-mandated good laboratory practices is

intuitively assumed to improve the quality of testresults, linking quality to compliance, as measured

by inspection, is difficult because of the lack of a

direct relationship. The only objective measurement

of quality in CLIA88 regulations is performance in

external quality assessment or PT programs. The

Centers for Medicare and Medicaid Services (CMS)

website claims that PT is a measure of laboratory

quality and that PT performance is an indicator of a

laboratorys ability to provide quality patient test

results [7]. This official, government-sponsored, web

site also declares that test accuracy, as assessed by PT:(1) reduces repetitive testing, (2) aids in rapid and

appropriate patient diagnoses, (3) contributes to ef-

fective treatment and (4) reduces overall costs of

medical care. The CMS concludes that the review of

a laboratorys PT performance data educates the

laboratory staff. This educational purpose closely

parallels and further validates the premise first dis-

cussed by Belk and Sunderman, who beginning in

1946, demonstrated that mere PT participation moti-

vated laboratories to improve performance [8]. Most

S.S. Ehrmeyer, R.H. Laessig / Clinica Chimica Acta 346 (2004) 374338


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importantly, now as then, a laboratory, which fails PT

by reporting wrong results, is better able to recog-

nize and presumably correct a performance problem.

A fundamental assumption, then and embodied inCLIA88, is that a performance problem identified

by PT is also present in patient test results. Belk and

Sundermans findings motivated the College of Amer-

ican Pathologists to offer, for educational purposes,

PT surveys beginning in 1947. Twenty years later, the

US government mandated PT participation as part of

the CLIA67 requirements governing 12,000 large

hospital and reference laboratories [5,9]. CLIA88

extended mandatory PT to all non-waived testing

sites.

The CLIA 88 mandated, analyte specific, PT

tolerance limits for selected chemistry analytes are

shown in Table 1 along with examples of acceptable

performance ranges for stated target values. These

tolerance limits are total error standards that incorpo-

rate both inaccuracy and imprecision and are defined

as either fixed limits (target valueF an absolute per-

centage of the target value) or target valueF a multi-

ple (usually 3.0) of the PT group standard deviation.

For example if the target value for sodium is 140

mmol/l, using the CLIA88 tolerance limit of 4.0

mmol/l, a laboratorys PT result to be acceptable

must fall within the range of 136144 mmol/l. EachPT event includes five samples for an analyte. Ac-

ceptable performance in a single event is achieving at

least four out of five correct results (>80% correct

performance). More than one incorrect result ( < 80%

correct) constitutes a failed analyte in that PT event.

Because CLIA88 only identifies one objective

measurement of quality, subjective indicatorsthe

frequency of inspection deficiencies and government

sanctionsalso were evaluated. CLIA88 requireslaboratories to be inspected every 2 years. The

inspectors look for compliance with the mandated,

good laboratory practices. Inspectors also determine

the degree to which total quality management con-

cepts, such as regular assessment of the total testing

process by the laboratory director, are incorporated

into the laboratory operation. Conceptually, the in-

spection process is viewed as a quality improvement

opportunity. Laboratories cited for deficiencies during

inspection must correct them. Most laboratories read-

ily comply, but a small percentage chooses not to

rectify deficiencies. These laboratories are subject to

sanctions on re-inspection. The most severe sanction

is revocation of the CLIA-certificate.

One of the most subjective of the CLIA88 require-

ments is that the laboratory director must assure that

the quality (accuracy, precision, long term stability,

sensitivity, specificity, etc.) of test results meets the

physicians needs. This makes the laboratory an active

participant in patient care. A recent study suggests that

US medical care, including the laboratory compo-

nents, may be falling short of its quality goal.

3. Results and discussion

Tables 2a 2c summarize PT participant perfor-

mance data for three events in 1994, one event in

1997 through 1999, and three PT events in 2002. The

Wisconsin State Laboratory of Hygiene PT Program is

one of 14 CLIA-approved programs [7]. Participants

are primarily from smaller hospital and physician

office laboratories. Data for six chemistry analytes

were selected because of the highest incidence of PTfailures. The PT data, spanning 8 years, show that

laboratory performance, evidenced by a decreased

percentage of failures, has improved and indicates

that laboratories can and do correct problems. The

mean failure rate for the six analytes over this 8-year

period has decreased roughly by a factor of 3.

Our studies provide some insight into intra-labora-

tory performance requirements necessary to pass PT

[1012]. Through computer modeling techniques and

direct statistical calculations, we demonstrated that the

Table 1

CLIA88 proficiency testing, tolerance limits and acceptable

performance (AP) ranges

Test or analyte CLIA88 tolerance limit (TL) AP= VFTL

Albumin TL = 10%, If TV = 40 g/l;

AP=3644 g/l

Calcium, total TL= 0.25 mmol/l, If TV= 2.20 mmol/l;

AP= 1.95 2.45 mmol/l

Cholesterol, total TL= 10%, If TV= 5.0 mmol/l;

AP= 4.5 5.5 mmol/l

Glucose TL = 10%, If TV = 6.7 mmol/l;

AP= 6.03 7.37 mmol/l

Sodium TL = 4 .0 mmol/l, If TV = 140.0 mmol/l;

AP= 136 144 mmol/l

Urea nitrogen TL=9%, If TV= 6.0 mmol Urea/l;

AP= 5.46 5.54 mmol Urea/l

S.S. Ehrmeyer, R.H. Laessig / Clinica Chimica Acta 346 (2004) 3743 39


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PT criteria could be translated directly into total

allowable error, or intra-laboratory performance

specifications. These consist of maximum allowablecoefficient of variation (CV) and bias combinations.

Statistically, a laboratory with no bias (inaccuracy)

and a day-to-day CV (imprecision) equal to one-third

of the specified PT criterion has virtually a 100%

chance of passing a 5-sample PT event for that

analyte. For example, the PT criterion for both glucose

and cholesterol is target valueF 10%. A laboratory

having a methodology with no bias and a CV that is

100% of the specified PT limit (i.e., an internal CV of

10% of the target value for either glucose or choles-

terol) would fail PT (achieve < 80% correct results in

one PT event) 51% of the time. This is tantamount tofailing every other PT event. If the laboratory reduces

its internal CV for glucose or cholesterol to 5% of the

target value, or to one-half of the PT limit, the chance

of a single event failure is dramatically reduced to

about 2%, or one in 50 PT events. Most importantly, if

the CV is reduced to one-third of the PT limit, the

chance of achieving < 80% correct results in one PT

event is virtually zero. This assumes that the labora-

tory is in statistical control, i.e., the method is func-

tioning properly. It clearly delineates the apparent

CLIA88 mandated view of what constitutes adequate

performance.

For regulatory purposes, CLIA88 defines passing

PT as being successful in two out of three consecutive

PT events. Our studies show that a laboratory having

no bias will pass PT, long term, with a CV of

approximately 40% of the specified CLIA88 limits.

However, passing PT does not necessarily indicate

that a laboratorys results are good enough to meet

the needs of the physician. There are no data to

support the assumption that a laboratory successfully

passing PT is providing physicians with clinically

relevant data. The PT criteria defining successfulperformance (Table 1) are open to question, since

they are primarily based on 19851990 state-of-the-

art interlaboratory performance data.

A the critical level of 5 mmol/l for cholesterol, we

can assume that among laboratories passing PT, some

are doing so with day-to-day CVs at or near 40% of

the CLIA88 tolerance limit or 0.2 mmol/l. This also

means that a cholesterol result of 5.0 mmol/l would be

reported, 5% of the time, as >5.4 or < 4.6 mmol/l. The

question is will data with this amount of inherent

variation permit adequate diagnosis and treatmentsuch as prescribing a cholesterol-lowering drug.

As seen in Tables 2a 2c, the number of partic-

ipants from 1994 to 2002 has significantly decreased.

This reflects the fact that some test sites have

changed PT providers while others have shifted from

moderate and high complexity test methods to

waived testing methodologies, which do not re-

quire participation in PT. Likewise, some poorer

performing laboratories, those failing PT, have dis-

continued laboratory testing entirely. The latter case

Table 2a

Participant failures (%) in Wisconsin PT program1994

PT event #1 PT event #2 PT event #3

% N % N % NAlbumin 9 223 7 223 3 232

Calcium 10 314 8 314 5 323

Cholesterol 15 1094 12 1083 11 1057

Glucose 12 1099 7 1080 8 1060

Sodium 17 479 18 476 16 481

Urea nitrogen 14 851 4 768 5 738

Mean failure rate for these six analytes over 3 PT even-

ts= 10.1F 4.6.

Table 2b

Participant failures (%) in Wisconsin PT program1997 1999

PT event

#1 (97)

PT event

#1 (98)

PT event

#1 (99)

% N % N % N

Albumin 3 232 2 219 0 224

Calcium 5 260 4 245 1 244

Cholesterol 6 926 5 690 2 548

Glucose 6 827 4 679 3 602

Sodium 7 374 8 356 4 352

Urea nitrogen 9 508 7 469 1 428

Mean failure rate for these six analytes over 3 PT events= 4.3F 2.6.

Table 2c

Participant failures (%) in Wisconsin PT program2002

PT event #1 PT event #2 PT event #3

% N % N % NAlbumin 2 301 1 302 5 304

Calcium 1 333 1 222 2 337

Cholesterol 4 436 4 428 3 417

Glucose 8 502 5 500 4 497

Sodium 3 375 4 372 5 374

Urea nitrogen 3 415 3 413 4 413

Mean failure rate for these six analytes over 3 PT events = 3.4F 1.8.



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could be regarded as a CLIA-induced improvement

in the quality of testing.

The percentages of test sites with CLIA88

inspection deficiencies are shown in Table 3. Thereis a decline in the percentage of laboratories cited

for deficiencies over the last four inspection cycles

(approximately 8 years). Before declaring the

CLIA88 approach to ensuring quality through

enforced compliance to be evidence of success, it

must be noted that the number of laboratories

inspected for CLIA88 compliance has dropped over

this period from 37,000 in 1995 to 22,000 in 2002.

The reason for the decline of 15,000 laboratories is

uncertain. Some test sites undoubtedly stopped

testing entirely while others have chosen to be

inspected by other government-approved profession-

al programs such as the Joint Commission on

Accreditation of Healthcare Organizations, the Col-

lege of American Pathologists, or COLA (formerly

the Commission of Office Laboratory Testing). Still

others, particularly physician office laboratories,

have abandoned CLIA-classified moderate and high

complexity test methodologies and now perform

only CLIA-waived testing that does not require

CLIA88 inspections. Today, the waived list of tests

includes 72 analytes and 1410 test systems, which

provide testing in most disciplines of laboratorymedicine [7,13]. As a result, analytes such as

hemoglobin Alc, HDL cholesterol and H. pylori

are available to test sites that want to provide

testing services, but do not wish to be CLIA

inspected or participate in mandatory PT.

Government sanctions imposed on laboratories not

correcting identified CLIA88 deficiencies are sum-

marized in Table 4. These data are difficult to interpret

because of the very small percentage of laboratories

sanctioned for repeated violations. The 1996 2002

increase in the frequency of citations is possibly due

to fewer laboratories surveyed (37,000 versus 22,000)

and to inspectors becoming more willing to issue

sanctions. In the inspectors view most test sites have

11 years experience with the CLIA88 requirements

and should be in compliance.

The last indicator considered was determiningwhether the quality of test results, as a result of

universal adoption of CLIA88 requirements, better

meet customers (physicians and patients) needs.

According to the 2000 U.S. Institute of Medicine

(IOM) report, To Err is Human: Building a Safer

Health System, between 44,000 and 98,000 hospi-

talized Americans die each year from a variety of

preventable medical errors [14]. Some portion of

these serious medical errors must be attributed, in

full or in part, to failures in the laboratory testing

process. Beginning with Belk and Sunderman, thereis overwhelming data to support the idea that

problems in laboratory testing are not due to a

failure to appreciate the need for quality test results.

Rather, the critical concern is how to better manage

the testing process to ensure that the appropriate

level of quality is achieved. Simply mandating, by

regulation, specific quality practices such as those in

CLIA88 does not appear to be the entire answer.

The IOM study recommends several general solu-

tions for building a better and safer health care

Table 3

Most frequently cited CLIA inspection deficiencies (%) [7]

Deficiencies f 1995

1996af 1997

1998

f 1999

2000

f 2001

2002b

Failure to

run QC

30% 27% 24% 18%

Failure to

follow

manufacturers

directions

13% 12% 15% 6%

No quality

assurance

program

7% 7% 9% 3%

Failure of

laboratory

director to

meet

responsibilities

6% 8% 9% 2%

a Approximately 37,000 CLIA inspected test sites.b Approximately 22,000 CLIA inspected test sites.

Table 4

Percent (%) of CLIA-inspected laboratories issued sanctions in

1996 and 2002 for failure to correct deficiencies [7]

Sanctions 1996a 2002b

CLIA certificate

suspensions, limitations

or revocations

0.19% 0.36%

Test sites fined or

given directed plans

of corrections

0.01% 0.13%

a Approximately 37,000 CLIA inspected test sites.b Approximately 22,000 CLIA inspected test sites.



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system. It specifically recommends incorporating

safeguards that mandate the use of quality processes

to ensure quality and reduce the likelihood of

human err. This can apply fully to the testingprocess governed by the CLIA88 regulations. Con-

ceptually, CLIA88 envisioned a unique, total qual-

ity management partnership among regulators,

manufacturers, and laboratorians to achieve quality

laboratory testing [15]. In the 11-years post CLIA,

we have witnessed the evolution of test systems by

which, to a lesser or greater extent, manufacturers

have taken the testing process out of the hands of

testing personnel and have produced instruments

capable of delivering assured quality. Examples

exist of systems with internal liquid calibrators and

controls that use sophisticated analytical algorithms.

These systems perform the calibration, but also run

the controls, assess performance, rectify problems

and, then and only then, release patient test results

[16]. Certainly this new generation of instruments is

in part due to the manufacturers desire to sell more

testing systems by helping customers meet CLIA88

quality requirements.

4. Conclusions

In the last analysis, the fundamental question

remains, Do fewer PT failures, fewer inspection

deficiencies, and a very limited number of govern-

ment sanctions mean that the quality of patient test

results has improved? Intuitively we all believe

that adhering to the CLIA88-mandated, good labo-

ratory practices and passing PT improves laboratory

test quality. The indicators assessed in this study

generally support this conclusion. However, the

direct link between regulatory compliance and qual-

ity test results is difficult to prove. Clearly, thedecision to make PT the cornerstone of CLIA88

compliance has been a good one. The success of PT

as a quality tool has been demonstrated by over 50

years of experience.

A laboratorys motivation may not reflect a true

quality goal in the total quality management or

ISO spirit though the outcome is desirable. Adop-

tion of good laboratory practices and successful PT

performance, if only to achieve and retain CLIA-

certification, most certainly improves test quality.

Other laboratories do benefit from the guidance pro-

vided by the CLIA88 regulations. At a minimum,

there is strong suggestive evidence that bad laborato-

ries are selectively pushed out of the testing businessor, as an alternate hypothesis, have become better

performers. The small numbers of government im-

posed sanctions, one-tenth of one percent; speak to the

laboratories overwhelming commitment to do good

quality laboratory work.

While our overall assessment is that compliance to

CLIA88, has improved US clinical laboratory perfor-

mance, we as scientists must distinguish what we

know from what we think (assume) we know.

References

[1] Public Law 100 578, Section 353 Public Health Service Act

(42 U.S.C. 263a) October 31, 1988. U.S. Department of

Health and Human Services.

[2] Medicare. Medicaid and CLIA programs: regulations imple-

menting the Clinical Laboratory Improvement Amendments

of 1988 (CLIA). Final rule. Fed Reg 1992;57:7002186.

[3] U.S. Department of health and Human Services. Medicare,

medicaid and CLIA programs; laboratory requirements relat-

ing to quality systems and certain personnel qualifications;

final rule. Fed Reg 2003;68:3640714.

[4] URL: http://www.iso.ch/.

[5] U.S. Department of Health. Education and Welfare, Public

Health Service, Center for Disease Control, 1967: Clinical

Laboratories Improvement Act of 1967. Part F of Title III of

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[7] http://www.cms.gov/clia/.

[8] Belk W, Sunderman W. A survey of the accuracy of chemical

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long term performance as successful, probation and

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