CMS Fed Reg PDF

Friday,
January 24, 2003
Part III
Department of
Health and Human
Services
Centers for Medicare & Medicaid Services
Centers for Disease Control and
Prevention
42 CFR Part 493

Medicare, Medicaid, and CLIA Programs;
Laboratory Requirements Relating to
Quality Systems and Certain Personnel
Qualifications; Final Rule
VerDate Dec<13>2002 19:58 Jan 23, 2003 Jkt 200001 PO 00000 Frm 00001 Fmt 4717 Sfmt 4717 E:\FR\FM\24JAR3.SGM 24JAR3
3640 Federal Register / Vol. 68, No. 16 / Friday, January 24, 2003 / Rules and Regulations
DEPARTMENT OF HEALTH AND 8155, Judith A. Yost (CMS), (410) 786– phase-in of certain requirements where
HUMAN SERVICES 3531. the comments supported taking this
SUPPLEMENTARY INFORMATION: action.
Centers for Medicare & Medicaid Copies: To order copies of the Federal The phased-in provision included
Services Register containing this document, send quality control (QC) requirements
your request to: New Orders, applicable to moderate complexity tests
Centers for Disease Control and Superintendent of Documents, P.O. Box and the date by which an individual
Prevention 371954, Pittsburgh, PA 15250–7954. with a doctorial degree must possess
Specify the date of the issue requested board certification to qualify as a
42 CFR Part 493 and enclose a check or money order director of a laboratory that performs
[CMS–2226–F] payable to the Superintendent of high complexity testing.
Documents, or enclose your Visa or During the phase-in, the Food and
RIN 0938–AK24 Master Card number and expiration Drug Administration (FDA) was to
date. Credit card orders can also be establish a process to review and clear
Medicare, Medicaid, and CLIA placed by calling the order desk at (202) manufacturers’ QC instructions for CLIA
Programs; Laboratory Requirements 512–1800 or by faxing to (202) 512– QC purposes. Because the CLIA program
Relating to Quality Systems and 2250. The cost for each copy is $9. As is user fee funded, we decided it would
Certain Personnel Qualifications an alternative, you can view and be prudent to wait until the phase-in
AGENCY: Centers for Disease Control and photocopy the Federal Register period ended before implementing the
Prevention (CDC) and Centers for document at most libraries designated FDA QC review. This afforded us the
Medicare & Medicaid Services (CMS), as Federal Depository Libraries and at survey experience necessary to
HHS. many other public and academic determine whether an additional FDA
ACTION: Final rule.
libraries throughout the country that review process beyond that already in
receive the Federal Register. place as part of the premarket review
SUMMARY: This final rule revises and This Federal Register document is would be of benefit to laboratories. We
responds to comments on certain also available from the Federal Register realized through our experience
laboratory requirements issued pursuant online database through GPO Access, a inspecting laboratories that an
to the Clinical Laboratory Improvement service of the U.S. Government Printing additional FDA review would not be of
Amendments of 1988 (CLIA), Pub. L. Office. This Web site address is: http:/ such benefit. We decided to remove this
100–578. Specifically, this final rule sets /www.access.gpo/nara/index.html. prospective provision. Therefore, we are
forth requirements for certain quality I. Background removing all references to the FDA CLIA
control (QC) provisions and personnel QC clearance process that was not
On February 28, 1992, we published
qualifications; consolidates and implemented.
a final rule with comment period in the
reorganizes the requirements for patient The phase-in effective dates contained
Federal Register (57 FR 7002) that set
test management, QC, and quality in the February 28, 1992 final rule with
forth the requirements for laboratories
assurance; and changes the consensus comment period were further extended
that are subject to the Clinical
required for grading proficiency testing in the final rules with comment period
Laboratory Improvement Amendments
challenges. published on December 6, 1994 in the
of 1988 (CLIA).
To ensure a smooth transition to the Under the provisions of the sentence Federal Register (59 FR 62606), May 12,
new provisions for directors of high following section 1861(s)(15) through 1997 in the Federal Register (62 FR
complexity testing who are not board 1861(s)(17) of the Social Security Act, 25855), October 14, 1998 in the Federal
certified (but who have doctoral (the Act) any laboratory that wants to be Register (63 FR 55031), and December
degrees), we will not be holding paid for services furnished to Medicare 29, 2000 in the Federal Register (65 FR
facilities out of compliance with the beneficiaries must meet the 82941).
provisions of the rule concerning requirements of section 353 of the The extensions allowed previously
directors who are not board certified Public Health Services Act. Subject to unregulated laboratories time to
until the effective date of this new rule, specified exceptions, all laboratories, understand and implement these
to the extent the facilities are otherwise regardless of whether they receive requirements. The extensions also
in compliance with the requirements for payment from the Medicare or Medicaid provided the Department of Health and
laboratory directors. programs must have a current and valid Human Services (HHS) additional time
EFFECTIVE DATES: This final rule is CLIA certificate to test human to issue revised QC requirements,
effective on April 24, 2003, except specimens. The February 28, 1992 final review board certification program
§ 493.1443(b)(3) is effective on February rule with comment period established requests for approval, and ensure that
24, 2003. uniform requirements based on the laboratory directors with a doctoral
Compliance Dates: To ensure a clear complexity of testing performed by degree had sufficient time to
transition from the board certification laboratories regardless of the successfully complete the requirements
provisions of the former rule at 42 CFR laboratory’s location, size, or type. In for board certification.
493.1443(b)(2) that have a compliance the interest of public health, we On December 28, 2001, we published
date of December 31, 2002 (as set forth included requirements in the February a proposed rule in the Federal Register
in 65 FR 82941), we will not be holding 28, 1992 final rule with comment period (66 FR 67163) seeking comments on
facilities out of compliance with the to ensure the quality of laboratory provisions to revise and expand the
former rule until the effective date of the services. qualification requirements by which an
parallel provisions of this new rule to We recognized that it would take time individual with a doctoral degree in a
the extent that facilities are otherwise in and resources for laboratories to chemical, physical, biological, or
compliance with the regulations for understand and to implement the new clinical laboratory science from an
laboratory directors. requirements contained in the February accredited institution may qualify to
FOR FURTHER INFORMATION CONTACT: 28, 1992 final rule with comment serve as a director of a laboratory
Rhonda S. Whalen (CDC), (770) 488– period. This final rule completes the performing high complexity testing. The
Federal Register / Vol. 68, No. 16 / Friday, January 24, 2003 / Rules and Regulations 3641
three proposed alternative qualification renamed, reorganized, and consolidated been revised to allow CLIA-certified
pathways were as follows: similar requirements into one section, laboratories to refer specimens to
• On or after January 1, 2003, be deleted duplicate requirements, and laboratories operated under the Veterans
certified and continue to be certified by reworded numerous requirements to Administration (VA), the Department of
a board approved by HHS. maintain and/or clarify their original Defense (DOD), and CLIA-exempt
• Before January 1, 2003, must have intent, making the revised regulation laboratories within a State whose
served or be serving as a director of a easier to read and understand. In licensure program has been granted
laboratory performing high complexity addition to specific changes to subparts approval under subpart E.
testing and must have at least 2 years of I, J, K, M, and P, applicable technical Requirements pertaining to the total
laboratory training or experience, or and conforming changes were also made testing process (preanalytic, analytic,
both; and 2 years experience directing to other subparts. and postanalytic) are now in subpart K.
or supervising high complexity testing. The organization of this regulation Specifically, subpart K has been revised
• Have at least 6 years of laboratory now reflects the flow of a patient to eliminate the QC requirements
training or experience, or both, specimen through the laboratory, that is, formerly at § 493.1202 and provisions
including 2 years of experience from receipt of the specimen with the pertaining to the FDA review and
directing or supervising high test request through test performance approval of manufacturers’ test system
complexity testing. and test result reporting. In addition, QC for CLIA purposes as specified at
In this final rule, effective April 24, this final rule more accurately describes § 493.1203 in the February 28, 1992
2003, all laboratories must meet and the testing requirements and laboratory final rule with comment period. Also,
follow the QC requirements. In addition, assessment activities. subpart K is now structured to correlate
we are setting forth qualification In this final rule, the former Subpart with the movement of a specimen
requirements for an individual with a I—Proficiency Testing Programs for through the laboratory from acquisition
doctoral degree to serve as a director of Tests of Moderate Complexity to examination or testing, and reporting
a laboratory performing high complexity (Including the Subcategory), High of results. The requirements were not
testing. Effective February 24, 2003, an Complexity, or Any Combination of substantively changed to correspond to
individual with a doctoral degree may These Tests has been renamed the testing process, but we did eliminate
qualify to serve as a director of a Proficiency Testing Programs for redundant requirements and revise
laboratory that performs high Nonwaived Testing. In addition, in each others for clarification.
complexity testing if he or she is specialty and subspecialty area of the In addition, subpart K now
certified and continues to be certified by subpart, we are restoring the incorporates the requirements formerly
a board approved by HHS; or before the requirement for the 80 percent in Subpart P—Quality Assurance;
effective date of this rule, has served or agreement used by proficiency testing Moderate Complexity (Including the
is serving as a director of a laboratory programs prior to the February 28, 1992 Subcategory) or High Complexity
performing high complexity testing and final rule with comment period. Testing, or Any Combination of These
has acquired at least 2 years of The requirements formerly in Subpart Tests. These requirements are now
laboratory training or experience, or J—Patient Test Management for located under the appropriate sections
both, and 2 years of experience directing Moderate Complexity (Including the in subpart K, that is, General Laboratory
or supervising high complexity testing. Subcategory), High Complexity, or Any Systems, Preanalytic Systems, Analytic
The qualification requirements for Combination of These Tests; Subpart Systems, and Postanalytic Systems. We
high complexity laboratory directors K—Quality Control for Tests of listed the quality assurance (renamed
that are contained in this final rule will Moderate Complexity (Including the quality assessment (QA) to more clearly
become effective February 24, 2003. To Subcategory), High Complexity, or Any reflect the activities performed)
ensure a smooth transition to these new Combination of These Tests; and activities for each phase of testing. For
provisions, we will not be holding Subpart P—Quality Assurance for example, QA requirements for
facilities out of compliance with the Moderate Complexity (Including the preanalytic activities, such as
Board certified regulations of the former Subcategory) or High Complexity monitoring the medical necessity and
rule until the effective date of this new Testing, or Any Combination of These completeness of test request information
rule, to the extent the facilities are Tests, are consolidated and reorganized solicited and obtained by the laboratory,
otherwise in compliance with the into a new Subpart J—Facility now appear at the end of the preanalytic
regulations for laboratory directors. Administration for Nonwaived Testing, section of subpart K under § 493.1249.
In addition, we are addressing the and Subpart K—Quality Systems for We believe that integrating the QA
comments received in response to the Nonwaived Testing. requirements into the various phases of
February 28, 1992 final rule with As revised by this issuance, subpart J the testing process enhances the
comment period concerning part 493 of consolidates and clarifies the facility understanding of the vital and
title 42 of the Code of Federal administration requirements for important role QA plays in ensuring
Regulations (CFR), subparts I, J, K, M, laboratories performing nonwaived that quality services are provided by the
and P; comments received in response testing. These include requirements for laboratory throughout the entire testing
to the date-extension rules for certain facility space, utilities and safety, process. To further emphasize and
provisions of subparts K and M; and transfusion services, and record and clarify the essential components of a
comments to the December 28, 2001 specimen retention. Also, subpart J now comprehensive QA program, we are
proposed rule regarding qualification specifies that laboratories must comply reiterating in each assessment section
requirements for directors of with Federal, State, and local laboratory the laboratory’s responsibility to: (1)
laboratories performing high complexity requirements. This will allow CMS to Establish and follow written polices and
testing. support a Federal, State, or local procedures for an ongoing mechanism
government that seeks to protect the to monitor and assess each of its
II. Highlights and Organization of Final public from actions it finds would be activities; (2) take corrective actions, as
Rule detrimental to public health. In necessary, based on these assessments;
This regulation contains revisions to addition, the requirements formerly at (3) review the effectiveness of the
part 493 of title 42 of the CFR. We have § 493.1111 (now at § 493.1242(c)) have assessments and corrective actions
taken; (4) revise policies and § 493.1443(b)(3)(i) by removing the III. Distribution Table
procedures, as necessary, to prevent reference to specific boards approved by
recurrences of problems; (5) discuss the HHS. All HHS-approved boards are The following crosswalk table enables
assessment activities and findings with listed on the Internet at http:// the reader to easily locate where the
the appropriate staff; and (6) document cms.hhs.gov/clia/dirc/con.asp. HHS- requirements from the former rule have
all assessment activities. To ensure the approved boards will also be listed in been relocated. It lists the former section
clarity of this final rule, many of the QA Appendix C of the State Operations titles along with the section titles as
requirements from the former subpart P Manual (CMS Pub. 7), subpart M. This they appear in this final rule. In
had to be rewritten. change will allow greater flexibility to addition, the reorganized regulation
To conform with the names of the update the list of HHS-approved boards. now follows the path of patient
new subparts I, J, and K, the former specimens as they proceed through the
Also, we are announcing two new HHS-
Subpart M—Personnel for Moderate clinical laboratory. This organizational
approved boards; the National Registry
Complexity (Including the Subcategory) structure was adopted at the
for Clinical Chemistry at the doctoral
and High Complexity Testing has been recommendation of the Clinical
renamed Personnel for Nonwaived level and the American Board of
Forensic Toxicology. Laboratory Improvement Advisory
Testing. In subpart M, we are finalizing Committee to assist laboratories in
the qualification requirements for To clarify these changes, we have
better understanding the basic CLIA
directors of laboratories performing high provided a distribution table, which
requirements.
complexity testing at § 493.1443(b)(3). contains a detailed list of sections that
In addition, we are revising have been removed or redesignated.
TABLE.—CROSSWALK
Former requirements and former sections (part Requirements in this final rule (part 493, sub- Sections in this final rule
493, subparts J, K, M, and P) parts J, K, and M)
Patient test management; moderate complexity

(including the subcategory), or high com-
plexity testing, or any combination of these
tests:
§ 493.1101—Introductory text ..................... Specimen identification and integrity ............... §§ 493.1232;
Preanalytic systems ......................................... 493.1240;
Postanalytic systems ....................................... 493.1290
Procedures for specimen submission and han-
dling:
§ 493.1103(a) .............................................. Specimen identification and integrity ............... §§ 493.1232;
Specimen submission, handling, and referral 493.1242(a)(1) through (a)(6);
Procedure manual ............................................ 493.1251(b)(1)
§ 493.1103(b) .............................................. Specimen submission, handling, and referral §§ 493.1242(a)(8) and (d);
§ 493.1103(c) ............................................... Removed
Test requisition:
§ 493.1105—Introductory text ..................... Retention requirements .................................... §§ 493.1105(a)(1);
Test request ..................................................... 493.1241(a), (b), (c), and (d)
§ 493.1105(a) .............................................. Test request ..................................................... § 493.1241(c)(2)
§ 493.1105(b) .............................................. Test request ..................................................... § 493.1241(c)(1)
§ 493.1105(c) ............................................... Test request ..................................................... § 493.1241(c)(4)
§ 493.1105(d) .............................................. Test request ..................................................... § 493.1241(c)(6)
§ 493.1105(e) .............................................. Test request ..................................................... § 493.1241(c)(3) and (c)(7)
§ 493.1105(f) ............................................... Test request ..................................................... §§ 493.1241(c)(3), (c)(5), and (c)(8)
Specimen submission, handling, and referral 493.1242(a)(3)
Test records:
§ 493.1107—Introductory text ..................... Retention requirements .................................... §§ 493.1105(a)(3);
Specimen identification and integrity ............... 493.1232;
Test records ..................................................... 493.1283(a)(4) and (b)
§ 493.1107(a) .............................................. Test records ..................................................... § 493.1283(a)(1)
§ 493.1107(b) .............................................. Specimen submission, handling, and referral §§ 493.1242(b);
Test records ..................................................... 493.1283(a)(2)
§ 493.1107(c) ............................................... Test records ..................................................... § 493.1283(a)(3)
§ 493.1107(d) .............................................. Test records ..................................................... § 493.1283(a)(4)
Test report:
§ 493.1109—Introductory text ..................... Retention requirements .................................... §§ 493.1105(a)(3)(ii), (a)(6)(i), (a)(6)(ii) and
(b);
Postanalytic systems ....................................... 493.1290;
Test report ........................................................ 493.1291(b), (c)(3), and (f)
§ 493.1109(a) .............................................. Confidentiality of patient information ............... §§ 493.1231;
Postanalytic systems ....................................... 493.1290;
Test report ........................................................ 493.1291(a) and (c)(3)
§ 493.1109(b) .............................................. Test report ........................................................ §§ 493.1291(c)(2), (c)(4), and (c)(6)
§ 493.1109(c) ............................................... Test report ........................................................ § 493.1291(c)(7)
§ 493.1109(d) .............................................. Test report ........................................................ § 493.1291(d)
§ 493.1109(e) .............................................. Test report ........................................................ § 493.1291(f)
§ 493.1109(f) ............................................... Procedure manual ............................................ §§ 493.1251(b)(13);
Test report ........................................................ 493.1291(g)
TABLE.—CROSSWALK—Continued
§ 493.1109(g) .............................................. Test report ........................................................ § 493.1291(e)

§ 493.1109(h) .............................................. Test report ........................................................ § 493.1291(j)
Referral of specimens:
§ 493.1111—Introductory text ..................... Specimen submission, handling, and referral § 493.1242(c)
§ 493.1111(a) .............................................. Test report ........................................................ § 493.1291(i)(1)
§ 493.1111(b) .............................................. Test report ........................................................ § 493.1291(i)(2)
§ 493.1111(c) ............................................... Test report ........................................................ § 493.1291(i)(3)
General quality control; moderate complexity
(including the subcategory) or high com-
plexity testing, or any combination of these
tests:
§ 493.1201(a) .............................................. Removed
§ 493.1201(a)(1) .......................................... Removed
§ 493.1201(a)(2) .......................................... Facility Administration ...................................... §§ 493.1100
General laboratory systems ............................. 493.1230
Preanalytic systems ......................................... 493.1240
Analytic systems .............................................. 493.1250
Control Procedures .......................................... 493.1256(d)
Postanalytic systems ....................................... 493.1290
§ 493.1201(b) .............................................. Analytic systems .............................................. §§ 493.1250;
Moderate or high complexity testing, or both,
Effective from September 1, 1992 to Decem-
ber 13, 2000:
§ 493.1202(a) .............................................. Facility administration ...................................... §§ 493.1100;
Subpart K—Quality systems for nonwaived 493.1201 through 493.1227
testing.
§ 493.1202(b) .............................................. Facility administration ...................................... §§ 493.1100;
testing.
§ 493.1202(c) ............................................... Facility administration ...................................... §§ 493.1100;
testing.
§ 493.1202(c)(1) .......................................... Test systems, equipment, instruments, re- §§ 493.1252(a);
agents, materials, and supplies.
Maintenance and function checks ................... 493.1254(a)(1) and (a)(2)
Control procedures .......................................... 493.1256(d)(2)
§ 493.1202(c)(2) .......................................... Procedure manual ............................................ § 493.1251
§ 493.1202(c)(3) .......................................... Calibration and calibration verification proce- § 493.1255
dures.
§ 493.1202(c)(4) .......................................... Control procedures .......................................... § 493.1256
§ 493.1202(c)(5) .......................................... Control procedures .......................................... § 493.1256(d)(1)
§ 493.1202(c)(6) .......................................... Corrective actions ............................................ § 493.1282
§ 493.1202(c)(7) .......................................... Retention requirements .................................... § 493.1105(a)(3)
Moderate or high complexity testing, or both ef-
fective beginning 12/31/00:
§ 493.1203—Introductory text ..................... Removed
§ 493.1203(a) .............................................. Removed
§ 493.1203(b) .............................................. Removed
Facilities:
§ 493.1204—Introductory text ..................... Facilities ........................................................... § 493.1101(a)
§ 493.1204(a) .............................................. Facilities ........................................................... §§ 493.1101(a)(1) and (a)(2)
§ 493.1204(b) .............................................. Facilities ........................................................... § 493.1101(d)
Test methods, equipment, instrumentation, re-
agents, materials, and supplies:
§ 493.1205—Introductory text ..................... Facility Test systems, equipment, instruments, §§ 493.1101(b); 493.1252
reagents, materials, and supplies.
§ 493.1205(a) .............................................. Test systems, equipment, instruments, re- § 493.1252(a)
§ 493.1205(b) .............................................. Facilities ........................................................... § 493.1101(b)
§ 493.1205(c) ............................................... Test systems, equipment, instruments, re- § 493.1252(b)
§ 493.1205(c)(1) .......................................... Test systems, equipment, instruments, re- § 493.1252(b)
§ 493.1205(c)(1)(i) ....................................... Test systems, equipment, instruments, re- § 493.1252(b)(1)
§ 493.1205(c)(1)(ii) ...................................... Test systems, equipment, instruments, re- § 493.1252(b)(2)
§ 493.1205(c)(1)(iii) ..................................... Test systems, equipment, instruments, re- § 493.1252(b)(3)
§ 493.1205(c)(1)(iv) ..................................... Test systems, equipment, instruments, re- § 493.1252(b)(4)

§ 493.1205(c)(2) .......................................... Corrective actions ............................................ § 493.1282(b)(3)
§ 493.1205(d) .............................................. Test systems, equipment, instruments, re- § 493.1252(c)
§ 493.1205(d)(1) .......................................... Test systems, equipment, instruments, re- § 493.1252(c)(1)
§ 493.1205(e) .............................................. Test systems, equipment, instruments, re- § 493.1252(d)
§ 493.1205(e)(1) .......................................... Test systems, equipment, instruments, re- §§ 493.1252(d);
Immunohematology .......................................... 493.1271(b)
§ 493.1205(e)(2) .......................................... Test systems, equipment, instruments, re- § 493.1252(e)
Procedure manual:
§ 493.1211(a) .............................................. Procedure manual ............................................ § 493.1251(a)
§ 493.1211(b) .............................................. Procedure manual ............................................ § 493.1251(b)
§ 493.1211(b)(1) .......................................... Procedure manual ............................................ § 493.1251(b)(1)
§ 493.1211(b)(3) .......................................... Procedure manual ............................................ §§ 493.1251(b)(3);
Histocompatibility ............................................. 493.1278(d)(7)
§ 493.1211(b)(10) ........................................ Procedure manual ............................................ § 493.1251(b)(10)
§ 493.1211(b)(13) ........................................ Specimen submission, handling, and referral §§ 493.1242(a)(4);
§ 493.1211(c) ............................................... Procedure manual ............................................ § 493.1251(c)
§ 493.1211(d) .............................................. Procedure manual ............................................ § 493.1251(d)
§ 493.1211(e) .............................................. Procedure manual ............................................ § 493.1251(d)
§ 493.1211(f) ............................................... Procedure manual ............................................ § 493.1251(d)
§ 493.1211(g) .............................................. Retention requirements .................................... §§ 493.1105(a)(2);
Procedure manual ............................................ 493.1251(e)
Establishment and verification of method per-
formance specifications:
§ 493.1213(a) .............................................. Establishment and verification of performance § 493.1253(a)
specifications.
§ 493.1213(b)(1) .......................................... Removed
§ 493.1213(b)(2) .......................................... Establishment and verification of performance §§ 493.1253(b)(1) and (2)
specifications.
§ 493.1213(b)(2)(i) ....................................... Establishment and verification of performance §§ 493.1253(b)(1) and (b)(2)
specifications.
§ 493.1213(b)(2)(i)(A) .................................. Establishment and verification of performance §§ 493.1253(b)(1)(i)(A) and (b)(2)(i)
specifications.
§ 493.1213(b)(2)(i)(B) .................................. Establishment and verification of performance §§ 493.1253(b)(1)(i)(B) and (b)(2)(ii)
specifications.
§ 493.1213(b)(2)(i)(C) .................................. Establishment and verification of performance § 493.1253(b)(2)(iii)
specifications.
§ 493.1213(b)(2)(i)(D) .................................. Establishment and verification of performance § 493.1253(b)(2)(iv)
specifications.
§ 493.1213(b)(2)(i)(E) .................................. Establishment and verification of performance §§ 493.1253(b)(1)(i)(C) and (b)(2)(v)
specifications.
§ 493.1213(b)(2)(i)(F) .................................. Establishment and verification of performance §§ 493.1253(b)(1)(ii) and (b)(2)(vi)
specifications.
§ 493.1213(b)(2)(i)(G) .................................. Establishment and verification of performance § 493.1253(b)(2)(vii)
specifications.
§ 493.1213(b)(2)(ii) ...................................... Establishment and verification of performance § 493.1253(b)(3)

specifications.
§ 493.1213(c) ............................................... Establishment and verification of performance § 493.1253(c)
specifications.
Equipment maintenance and function checks:
§ 493.1215(a)—Title only ............................ Removed
§ 493.1215(a)(1) .......................................... Removed
§ 493.1215(a)(1)(i) ....................................... Removed
§ 493.1215(a)(1)(ii) ...................................... Removed
§ 493.1215(a)(2)—Lead-in only ................... Removed
§ 493.1215(a)(2)(i) ....................................... Maintenance and function checks ................... § 493.1254(b)(1)(i)
§ 493.1215(a)(2)(ii) ...................................... Maintenance and function checks ................... § 493.1254(b)(1)(ii)
§ 493.1215(a)(2)(iii) ..................................... Maintenance and function checks ................... § 493.1254(b)(1)(ii)
§ 493.1215(b) .............................................. Removed
§ 493.1215(b)(1) .......................................... Removed
§ 493.1215(b)(1)(i) ....................................... Removed
§ 493.1215(b)(1)(ii) ...................................... Removed
§ 493.1215(b)(2) .......................................... Removed
§ 493.1215(b)(2)(i) ....................................... Maintenance and function checks ................... § 493.1254(b)(2)(i)
§ 493.1215(b)(2)(ii) ...................................... Maintenance and function checks ................... § 493.1254(b)(2)(ii)
§ 493.1215(b)(2)(iii) ..................................... Maintenance and function checks ................... § 493.1254(b)(2)(ii)
Calibration and calibration verification proce-
dures:
§ 493.1217—Introductory text ..................... General Provisions—Definitions Calibration §§ 493.2; 493.1255
and calibration verification procedures.
§ 493.1217(a) .............................................. Removed
§ 493.1217(b)—Lead-in only ....................... Removed
§ 493.1217(b)(1) .......................................... Calibration and calibration verification proce- § 493.1255(a)
dures.
§ 493.1217(b)(1)(i) ....................................... Calibration and calibration verification proce- § 493.1255(a)(1)
dures.
§ 493.1217(b)(1)(ii) ...................................... Calibration and calibration verification proce- § 493.1255(a)(2)
dures.
§ 493.1217(b)(1)(ii)(A) ................................. Calibration and calibration verification proce- § 493.1255(a)(2)(ii)
dures.
§ 493.1217(b)(1)(ii)(B) ................................. Calibration and calibration verification proce- § 493.1255(a)(2)(i)
dures.
§ 493.1217(b)(1)(iii) ..................................... Calibration and calibration verification proce- § 493.1255(a)(3)
dures.
§ 493.1217(b)(2) .......................................... Calibration and calibration verification proce- § 493.1255(b)
dures.
§ 493.1217(b)(2)(i) ....................................... Calibration and calibration verification proce- § 493.1255(b)(1)
dures.
§ 493.1217(b)(2)(ii) ...................................... Calibration and calibration verification proce- § 493.1255(b)(2)
dures.
§ 493.1217(b)(2)(ii)(A) ................................. Calibration and calibration verification proce- § 493.1255(b)(2)(i)
dures.
§ 493.1217(b)(2)(ii)(B) ................................. Removed
§ 493.1217(b)(2)(ii)(B)(1) ............................. Removed
§ 493.1217(b)(2)(ii)(B)(2) ............................. Calibration and calibration verification proce- § 493.1255(b)(2)(ii)
dures.
§ 493.1217(b)(2)(ii)(C) ................................. Calibration and calibration verification proce- § 493.1255(b)(3)
dures.
§ 493.1217(b)(2)(ii)(C)(1) ............................. Calibration and calibration verification proce- § 493.1255(b)(3)(i)
dures.
§ 493.1217(b)(2)(ii)(C)(2) ............................. Calibration and calibration verification proce- § 493.1255(b)(3)(ii)
dures.
§ 493.1217(b)(2)(ii)(C)(3) ............................. Calibration and calibration verification proce- § 493.1255(b)(3)(iii)
dures.
§ 493.1217(b)(2)(ii)(C)(4) ............................. Calibration and calibration verification proce- § 493.1255(b)(3)(iv)
dures.
§ 493.1217(b)(3) .......................................... Calibration and calibration verification proce- § 493.1255(a) and (b)
dures.
Control procedures:
§ 493.1218 ................................................... Control procedures .......................................... § 493.1256(a)
§ 493.1218(a) .............................................. Removed
§ 493.1218(b)—Partial removed ................. Control procedures .......................................... § 493.1256(b), (c)(1), and (c)(2)
§ 493.1218(b)(1) .......................................... Control procedures .......................................... § 493.1256(d)(3)(ii)
§ 493.1218(b)(2) .......................................... Control procedures .......................................... § 493.1256(d)(3)(i)
§ 493.1218(b)(3) .......................................... Control procedures .......................................... § 493.1256(d)(5)
§ 493.1218(b)(3)(i) ....................................... Control procedures .......................................... § 493.1256(d)(5)

§ 493.1218(b)(3)(ii) ...................................... Control procedures .......................................... § 493.1256(d)(5)
§ 493.1218(b)(4) .......................................... Control procedures .......................................... §§ 493.1256(d)(3)(ii) and (d)(3)(iv)
§ 493.1218(b)(5) .......................................... Control procedures .......................................... § 493.1256(h)
§ 493.1218(c) ............................................... Control procedures .......................................... § 493.1256(d)(8)
§ 493.1218(d) .............................................. Control procedures .......................................... § 493.1256(d)(10)(i)
§ 493.1218(d)(1) .......................................... Control procedures .......................................... § 493.1256(d)(10)(ii)
§ 493.1218(d)(2) .......................................... Control procedures .......................................... § 493.1256(d)(10)(iii)
§ 493.1218(e) .............................................. Control procedures .......................................... § 493.1256(f)
§ 493.1218(f) ............................................... Control procedures .......................................... § 493.1256(e)
§ 493.1218(f)(1) ........................................... Control procedures .......................................... § 493.1256(e)(1)
§ 493.1218(f)(2) ........................................... Control procedures .......................................... § 493.1256(e)(2)
§ 493.1218(f)(3) ........................................... Control procedures .......................................... §§ 493.1256(e)(3);
Histopathology ................................................. 493.1273(a)
§ 493.1218(f)(4) ........................................... Control procedures .......................................... § 493.1256(e)(4)(5)
Remedial actions:
§ 493.1219—Introductory text ..................... Corrective actions ............................................ § 493.1282(a) and (b)
§ 493.1219(a) .............................................. Corrective actions ............................................ § 493.1282(b)(1)
§ 493.1219(a)(1) .......................................... Corrective actions ............................................ § 493.1282(b)(1)(i)
§ 493.1219(a)(2) .......................................... Corrective actions ............................................ § 493.1282(b)(1)(ii)
§ 493.1219(a)(3) .......................................... Corrective actions ............................................ § 493.1282(b)(1)(iii)
§ 493.1219(b) .............................................. Corrective actions ............................................ § 493.1282(b)(2)
§ 493.1219(c) ............................................... Test report ........................................................ § 493.1291(h)
§ 493.1219(d) .............................................. Test report ........................................................ § 493.1291(k)
§ 493.1219(d)(1) .......................................... Test report ........................................................ § 493.1291(k)(1)
§ 493.1219(d)(2) .......................................... Test report ........................................................ § 493.1291(k)(2)
§ 493.1219(d)(3) .......................................... Retention requirements .................................... §§ 493.1105(a)(6);
Test report ........................................................ 493.1291(k)(3)
Quality control records:
§ 493.1221 ................................................... Retention requirements .................................... § 493.1101(e);
493.1105(a)(3)(i) through (a)(3)(ii);
Test systems, equipment, instruments, re- 493.1252(b);
agents, material, and supplies performance.
Establishment and verification of performance 493.1253(c);
Maintenance and function checks ................... 493.1254(a), (b)(1)(ii), and (b)(2)(ii);
Calibration and calibration verification proce- 493.1255(a) and (b);
dures.
Control procedures .......................................... 493.1256(g);
Bacteriology ..................................................... 493.1261(c);
Mycobacteriology ............................................. 493.1262(c);
Mycology .......................................................... 493.1263(c);
Parasitology ..................................................... 493.1264(d);
Virology ............................................................ 493.1265(b);
Routine chemistry ............................................ 493.1267(d);
Hematology ...................................................... 493.1269(d);
Immunohematology .......................................... 493.1271(f);
Histopathology ................................................. 493.1273(f);
Cytology ........................................................... 493.1274(h);
Clinical Cytogenetics ........................................ 493.1276(e);
Histocompatibility ............................................. 493.1278(g)
Quality control-specialties and subspecialties
for tests of moderate or high complexity; or
both:
§ 493.1223 ................................................... Control Procedures .......................................... §§ 493.1256(a), (b), (c), (d)(1), and (2);
Microbiology:
§ 493.1225 ................................................... Removed
Bacteriology:
§ 493.1227—Introductory text ..................... Bacteriology ..................................................... § 493.1201
§ 493.1227(a)—Partially removed ............... Bacteriology ..................................................... § 493.1261(a)
Bacteriology:
§ 493.1227(a)(1)—Partially removed ........... Control procedures .......................................... §§ 493.1256(d)(3)(ii), (d)(3)(iv), and (e)(1);
Bacteriology ..................................................... 493.1261(a)(1)
§ 493.1227(a)(2) .......................................... Control procedures .......................................... §§ 493.1256(e)(1) and (e)(2);
Bacteriology ..................................................... 493.1261(a)(2)
§ 493.1227(a)(3) .......................................... Bacteriology ..................................................... § 493.1261(a)(3)
§ 493.1227(b) .............................................. Control procedures .......................................... § 493.1256(e)(1)
§ 493.1227(c) ............................................... Bacteriology ..................................................... § 493.1261(b)
§ 493.1227(c)(1) .......................................... Bacteriology ..................................................... § 493.1261(b)(2)
§ 493.1227(c)(2) .......................................... Bacteriology ..................................................... § 493.1261(b)(1)
Mycobacteriology:
§ 493.1229—Introductory text ..................... Mycobacteriology ............................................. § 493.1202
§ 493.1229(a) .............................................. Mycobacteriology ............................................. § 493.1262(a)

§ 493.1229(b) .............................................. Control procedures .......................................... § 493.1256(e)(3)
§ 493.1229(c) ............................................... Control procedures .......................................... §§ 493.1256(e)(2);
Mycobacteriology ............................................. 493.1262(a)
§ 493.1229(d) .............................................. Mycobacteriology ............................................. §§ 493.1262(b)(1) through (b)(3)
Mycology:
§ 493.1231—Introductory text ..................... Mycology .......................................................... § 493.1203
§ 493.1231(a) .............................................. Control procedures .......................................... §§ 493.1256(e)(1) and (e)(4)
§§ 493.1231(b) ............................................ Control procedures .......................................... § 493.1256(e)(1)
§ 493.1231(c) ............................................... Control procedures .......................................... § 493.1256(e)(2)
§ 493.1231(d) .............................................. Mycology .......................................................... §§ 493.1263(b)(1) through (b)(3)
Parasitology:
§ 493.1233—Introductory text ..................... Parasitology ..................................................... § 493.1204
§ 493.1233(a) .............................................. Parasitology ..................................................... § 493.1264(a)
§ 493.1233(b) .............................................. Parasitology ..................................................... § 493.1264(b)
§ 493.1233(c) ............................................... Parasitology ..................................................... § 493.1264(c)
Virology:
§ 493.1235—Introductory text ..................... Virology ............................................................ § 493.1205
§ 493.1235(a) .............................................. Facilities ........................................................... §§ 493.1101(b);
Test systems, equipment, instruments, re- 493.1252(a)
agents, material, and supplies.
§ 493.1235(b) .............................................. Virology ............................................................ §§ 493.1265(b);
Test records ..................................................... 493.1283(a)(4)
§ 493.1235(c) ............................................... Virology ............................................................ § 493.1265(a)
Diagnostic immunology:
§ 493.1237 ................................................... Removed
Syphilis serology:
§ 493.1239—Introductory text ..................... Syphilis serology .............................................. § 493.1207
§ 493.1239(a) .............................................. Test systems, equipment, instruments, re- § 493.1252(a)
§ 493.1239(b) .............................................. Control procedures .......................................... § 493.1256(d)(3)(iii)
§ 493.1239(c) ............................................... Control procedures .......................................... §§ 493.1256(a) and (d)(3)(ii);
§ 493.1239(d) .............................................. Control procedures .......................................... § 493.1256(f)
§ 493.1239(e) .............................................. Immunohematology .......................................... § 493.1271(b)
General immunology:
§ 493.1241 ................................................... General immunology ........................................ § 493.1208
§ 493.1241(a) .............................................. Control procedures .......................................... § 493.1256(d)(3)(iii)
§ 493.1241(b) .............................................. Control procedures .......................................... § 493.1256(a)
§ 493.1241(c) ............................................... Control procedures .......................................... § 493.1256(f)
§ 493.1241(d)—Lead-in only ....................... Removed
§ 493.1241(d)(1) .......................................... Immunohematology .......................................... § 493.1271(b)
§ 493.1241(d)(2) .......................................... Immunohematology .......................................... § 493.1271(b)
Chemistry:
§ 493.1243 ................................................... Removed
Routine chemistry:
§ 493.1245—Introductory text ..................... Routine chemistry ............................................ §§ 493.1210; 493.1267
§ 493.1245(a) .............................................. Routine chemistry ............................................ § 493.1267(a)
§ 493.1245(b) .............................................. Routine chemistry ............................................ § 493.1267(b)
§ 493.1245(c) ............................................... Routine chemistry ............................................ § 493.1267(b)
§ 493.1245(d) .............................................. Routine chemistry ............................................ § 493.1267(c)
Endocrinology:
§ 493.1247 ................................................... Endocrinology .................................................. § 493.1212
Toxicology:
§ 493.1249—Introductory text ..................... Toxicology ........................................................ §§ 493.1213;
Control procedures .......................................... 493.1256(d)(4)
§ 493.1249(a) .............................................. Control procedures .......................................... § 493.1256(d)(4)(i)
§ 493.1249(b) .............................................. Control procedures .......................................... § 493.1256(d)(4)(ii)
Urinalysis:
§ 493.1251—Introductory text only ............. Urinalysis .......................................................... § 493.1211
Hematology:
§ 493.1253 ................................................... Hematology ...................................................... § 493.1215
§ 493.1253(a) .............................................. Hematology ...................................................... §§ 493.1269(a)(1) and (a)(2)
§ 493.1253(b) .............................................. Control procedures .......................................... § 493.1256(d)
§ 493.1253(c) ............................................... Hematology ...................................................... § 493.1269(b)
§ 493.1253(d) .............................................. Hematology ...................................................... § 493.1269(c)
§ 493.1253(d)(1) .......................................... Hematology ...................................................... § 493.1269(c)(1)
§ 493.1253(d)(2) .......................................... Hematology ...................................................... § 493.1269(c)(2)
Pathology:
§ 493.1255 ................................................... Removed
Cytology:
§ 493.1257—Introductory text ..................... Cytology ........................................................... § 493.1221
§ 493.1257(a) .............................................. Cytology ........................................................... § 493.1274(b)

§ 493.1257(a)(1) .......................................... Cytology ........................................................... § 493.1274(b)(1)
§ 493.1257(a)(2) .......................................... Cytology ........................................................... § 493.1274(b)(2)
§ 493.1257(a)(3) .......................................... Cytology ........................................................... § 493.1274(b)(3)
§ 493.1257(a)(4) .......................................... Cytology ........................................................... § 493.1274(e)(4)
§ 493.1257(a)(5) .......................................... Cytology ........................................................... § 493.1274(a)
§ 493.1257(b) .............................................. Cytology ........................................................... § 493.1274(d)
§ 493.1257(b)(1) .......................................... Cytology ........................................................... §§ 493.1274(d)(2) and (d)(2)(iv)
§ 493.1257(b)(2) .......................................... Cytology ........................................................... § 493.1274(d)(2)(iii)
§ 493.1257(b)(3) .......................................... Cytology ........................................................... § 493.1274(g)
§ 493.1257(b)(3)(i) ....................................... Cytology ........................................................... § 493.1274(d)(2)(i)
§ 493.1257(b)(3)(ii) ...................................... Cytology ........................................................... § 493.1274(d)(2)(ii)
§ 493.1257(c) ............................................... Cytology ........................................................... § 493.1274(e)(1)
§ 493.1257(c)(1) .......................................... Cytology ........................................................... §§ 493.1274(e)(1)(i) through (e)(1)(v), and
(e)(2)
§ 493.1257(c)(2) .......................................... Cytology ........................................................... § 493.1274(e)(3)
§ 493.1257(c)(3) .......................................... Cytology ........................................................... § 493.1274(d)(1)(i)(B)
§ 493.1257(c)(4) .......................................... Cytology ........................................................... § 493.1274(d)(1)
§ 493.1257(c)(4)(i) ....................................... Cytology ........................................................... §§ 493.1274(d)(1)(i) and (d)(4)
§ 493.1257(c)(4)(ii) ...................................... Cytology ........................................................... § 493.1274(d)(1)(ii)
§ 493.1257(d) .............................................. Cytology ........................................................... § 493.1274(c)
§ 493.1257(d)(1) .......................................... Cytology ........................................................... § 493.1274(c)(1)
§ 493.1257(d)(1)(i) ....................................... Cytology ........................................................... § 493.1274(c)(1)(i)
§ 493.1257(d)(1)(ii) ...................................... Cytology ........................................................... § 493.1274(c)(4)
§ 493.1257(d)(1)(iii) ..................................... Cytology ........................................................... § 493.1274(c)(1)(ii)
§ 493.1257(d)(2) .......................................... Cytology ........................................................... § 493.1274(c)(2)
§ 493.1257(d)(3) .......................................... Cytology ........................................................... § 493.1274(c)(3)
§ 493.1257(d)(4) .......................................... Cytology ........................................................... §§ 493.1274(c)(5)(i) through (c)(5)(vi)
§ 493.1257(d)(5) .......................................... Cytology ........................................................... § 493.1274(c)(6)
§ 493.1257(e)—Lead-in only ....................... Removed
§ 493.1257(e)(1) .......................................... Cytology ........................................................... § 493.1274(e)(4)
§ 493.1257(e)(2) .......................................... Cytology ........................................................... § 493.1274(e)(5)
§ 493.1257(f) ............................................... Cytology ........................................................... § 493.1274(e)(6)
§ 493.1257(g) .............................................. Retention requirements, Cytology ................... §§ 493.1105(a)(7)(i)(A); 493.1274(f)(2) through
(f)(4)
Histopathology:
§ 493.1259—Introductory text ..................... Histopathology ................................................. § 493.1219
§ 493.1259(a) .............................................. Histopathology ................................................. § 493.1273(a)
§ 493.1259(b) .............................................. Retention requirements, Histopathology .......... §§ 493.1105(a)(7)(i)(B) and (a)(7)(ii);
493.1273(b)
§ 493.1259(c) ............................................... Facilities; Retention requirements, §§ 493.1101(e); 493.1105(a)(7)(iii);
Histopathology. 493.1273(b)
§ 493.1259(d) .............................................. Histopathology ................................................. § 493.1273(d)
§ 493.1259(e) .............................................. Histopathology ................................................. § 493.1273(e)
Oral pathology:
§ 493.1261 ................................................... Oral pathology .................................................. § 493.1220
Radiobioassay:
§ 493.1263 ................................................... Radiobioassay .................................................. § 493.1226
Histocompatibility:
§ 493.1265—Introductory text ..................... Histocompatibility ............................................. § 493.1227
§ 493.1265(a) .............................................. Histocompatibility ............................................. § 493.1278(f)
§ 493.1265(a)(1) .......................................... Histocompatibility ............................................. § 493.1278(e)(2)
§ 493.1265(a)(1)(i) ....................................... Histocompatibility ............................................. § 493.1278(e)(2)(i)
§ 493.1265(a)(1)(ii) ...................................... Histocompatibility; Procedure manual ............. §§ 493.1278(e)(1); 493.1251(b)(3)
§ 493.1265(a)(1)(iii) ..................................... Histocompatibility ............................................. § 493.1278(e)(2)(ii)
§ 493.1265(a)(1)(iv) ..................................... Procedure manual ............................................ §§ 493.1251(b)(3) and (b)(13)
§ 493.1265(a)(2) .......................................... Histocompatibility ............................................. § 493.1278(f)
§ 493.1265(a)(2)(i) ....................................... Histocompatibility ............................................. § 493.1278(f)(2)
§ 493.1265(a)(2)(ii) ...................................... Histocompatibility ............................................. §§ 493.1278(d)(4) through (d)(5)
§ 493.1265(a)(3)(i) ....................................... Test systems, equipment, instruments, re- § 493.1252(b);
Specimen submission, handling, and referral § 493.1242(a)(4)
§ 493.1265(a)(3)(ii) ...................................... Histocompatibility ............................................. § 493.1278(a)(1)
§ 493.1265(a)(3)(iii)—Partially removed ...... Specimen identification and integrity, §§ 493.1232; 493.1278(a)(2) 493.1283(a)(1)
Histocompatibility; Test records.
§ 493.1265(a)(4) .......................................... Histocompatibility ............................................. § 493.1278(a)(3)
§ 493.1265(a)(5) .......................................... Test systems, equipment, instruments, re- §§ 493.1252(c)(1) through (c)(4)
§ 493.1265(a)(6) .......................................... Histocompatibility ............................................. § 493.1278(b)
§ 493.1265(a)(6)(i) ....................................... Histocompatibility ............................................. § 493.1278(b)(2)
§ 493.1265(a)(6)(ii) ...................................... Histocompatibility ............................................. § 493.1278(b)(3)

§ 493.1265(a)(6)(iii) ..................................... Histocompatibility ............................................. § 493.1278(b)(5)(v)
§ 493.1265(a)(7) .......................................... Histocompatibility ............................................. § 493.1278(b)(5)
§ 493.1265(a)(7)(i) ....................................... Histocompatibility ............................................. § 493.1278(b)(5)(i)
§ 493.1265(a)(7)(ii) ...................................... Histocompatibility ............................................. § 493.1278(b)(5)(ii)
§ 493.1265(a)(7)(iii) ..................................... Histocompatibility ............................................. § 493.1278(b)(5)(iv)
§ 493.1265(a)(7)(iv) ..................................... Histocompatibility ............................................. § 493.1278(b)(5)(iii)
§ 493.1265(a)(8) .......................................... Histocompatibility ............................................. § 493.1278(d)
§ 493.1265(a)(8)(i) ....................................... Histocompatibility ............................................. § 493.1278(d)(5)
§ 493.1265(a)(8)(i)(A) .................................. Histocompatibility ............................................. § 493.1278(d)(5)
§ 493.1265(a)(8)(i)(B) .................................. Histocompatibility ............................................. § 493.1278(d)(5)
§ 493.1265(a)(8)(ii) ...................................... Histocompatibility ............................................. § 493.1278(d)(3)
§ 493.1265(a)(8)(ii)(A) ................................. Histocompatibility ............................................. § 493.1278(d)(3)
§ 493.1265(a)(8)(ii)(B) ................................. Test systems, equipment, instruments, re- § 493.1252(b)
§ 493.1265(a)(9)(i) ....................................... Histocompatibility ............................................. §§ 493.1278(b)(6) and (d)(6)
§ 493.1265(a)(9)(i)(A) .................................. Histocompatibility ............................................. §§ 493.1278(b)(6)(i) and (d)(6)(i)
§ 493.1265(a)(9)(i)(B) .................................. Histocompatibility ............................................. §§ 493.1278(b)(6)(ii) and (d)(6)(ii)
§ 493.1265(a)(9)(i)(C) .................................. Histocompatibility ............................................. § 493.1278(b)(6)(iii)
§ 493.1265(a)(9)(ii) ...................................... Histocompatibility ............................................. §§ 493.1278(c) and (e)(3)
§ 493.1265(a)(10) ........................................ Histocompatibility ............................................. §§ 493.1278(a) and (f)
§ 493.1265(a)(11) ........................................ Immunohematology .......................................... § 493.1271
§ 493.1265(a)(12) ........................................ Histocompatibility ............................................. § 493.1278(a)(4)
§ 493.1265(a)(13) ........................................ Removed
§ 493.1265(a)(14) ........................................ Histocompatibility ............................................. § 493.1278(a)(5)
§ 493.1265(b) .............................................. Histocompatibility ............................................. § 493.1278(f)
§ 493.1265(b)(1) .......................................... Histocompatibility ............................................. § 493.1278(f)(1)
§ 493.1265(c) ............................................... Histocompatibility ............................................. §§ 493.1278(a) through (c)
§ 493.1265(d) .............................................. Immunohematology .......................................... § 493.1271(b)
Clinical cytogenetics:
§ 493.1267—Introductory text ..................... Clinical cytogenetics ........................................ § 493.1225
§ 493.1267(a) .............................................. Cytogenetics .................................................... § 493.1276(c)
§ 493.1267(b) .............................................. Cytogenetics .................................................... §§ 493.1276(b)(1) through (b)(3)
§ 493.1267(c) ............................................... Cytogenetics .................................................... § 493.1276(a)
§ 493.1267(d) .............................................. Cytogenetics .................................................... § 493.1276(d)
Immunohematology:
§ 493.1269—Introductory text ..................... Immunohematology .......................................... § 493.1217
§ 493.1269(a) .............................................. Immunohematology .......................................... § 493.1271(a)(1)
§ 493.1269(b) .............................................. Immunohematology .......................................... § 493.1271(a)(2)
§ 493.1269(c) ............................................... Immunohematology .......................................... § 493.1271(a)(3)
§ 493.1269(d) .............................................. Immunohematology .......................................... § 493.1271(a)
Transfusion services and bloodbanking:
§ 493.1271—Partially removed ................... Requirements for transfusion services and § 493.1103; § 493.1449(b) and (q)
Subpart M.
Immunohematological collection, processing,
dating periods, labeling and distribution of
blood and blood products:
§ 493.1273—Introductory text ..................... Immunohematology .......................................... § 493.1271(b)
§ 493.1273(a) .............................................. Immunohematology .......................................... § 493.1271(b)
§ 493.1273(b) .............................................. Immunohematology .......................................... § 493.1271(b)
§ 493.1273(c) ............................................... Immunohematology .......................................... § 493.1271(b)
§ 493.1273(d) .............................................. Requirements for transfusion services ............ § 493.1103(c)(2)
Blood and blood products storage facilities:
§ 493.1275(a) .............................................. Immunohematology .......................................... § 493.1271(c)
§ 493.1275(a)(1) .......................................... Immunohematology .......................................... § 493.1271(c)(1)
§ 493.1275(a)(2) .......................................... Immunohematology .......................................... § 493.1271(c)(2)
§ 493.1275(b) .............................................. Requirements for transfusion services ............ § 493.1103(c)(1)
Arrangement for services:
§ 493.1277 ................................................... Requirements for transfusion services ............ § 493.1103(a)
Provision of testing:
§ 493.1279—Partially removed ................... Requirements for transfusion services ............ §§ 493.1103(b)
Retention of samples of transfused blood:
§ 493.1283 ................................................... Immunohematology .......................................... § 493.1271(d)
Investigation of transfusion reactions:
§ 493.1285 ................................................... Requirements for transfusion services; §§ 493.1103(d); 493.1271(e)(1)and (e)(2)
Immunohematology.
Quality assurance for Moderate Complexity (in-

cluding the Subcategory) or High Complexity
Testing, or Any Combination of These Tests:
§ 493.1701 ................................................... Introduction; General laboratory systems; §§ 493.1200; 493.1230; 493.1239; 493.1240;
General laboratory systems assessment; 493.1241(e); 493.1249; 493.1250;
Preanalytic Systems; Test request; 493.1289; 493.1290; 493.1299
Preanalytic systems assessment; Analytic
Systems; Analytic systems assessment;
Postanalytic Systems; Postanalytic systems
assessment.
Patient test management assessment:
§ 493.1703—Introductory text ..................... General laboratory systems; General labora- §§ 493.1230; 493.1239(a) and (b); 493.1240;
tory systems assessment; Preanalytic Sys- 493.1249(a) and (b); 493.1290; 493.1299(a)
tems; Preanalytic systems assessment; and (b)
Postanalytic Systems; Postanalytic systems
assessment.
§ 493.1703(a) .............................................. Preanalytic systems assessment ..................... §§ 493.1249(a) and (b)
§ 493.1703(b) .............................................. Preanalytic systems assessment ..................... §§ 493.1249(a) and (b)
§ 493.1703(c) ............................................... Preanalytic systems assessment ..................... §§ 493.1249(a) and (b)
§ 493.1703(d) .............................................. Postanalytic systems assessment ................... §§ 493.1299(a) and (b)
§ 493.1703(e) .............................................. Test Report; Postanalytic systems assess- §§ 493.1291(a), (g), and (h); 493.1299(a) and
ment. (b)
§ 493.1703(f) ............................................... Facilities; Postanalytic systems assessment ... §§ 493.1101(e) 493.1299(a) and (b)
Quality control assessment:
§ 493.1705—Introductory text ..................... Analytic Systems; Analytic system assess- §§ 493.1250; 493.1289(a) and (b)
ment.
§ 493.1705(a) .............................................. Analytic system assessment ............................ §§ 493.1289(a) and (b)
§ 493.1705(b) .............................................. Analytic system assessment ............................ §§ 493.1289(a) and (b)
§ 493.1705(c) ............................................... Analytic system assessment; Postanalytic §§ 493.1289(a) and (b); 493.1299(a) and (b)
systems assessment.
Proficiency testing assessment:
§ 493.1707 ................................................... General laboratory systems; Evaluation of §§ 493.1230; 493.1236(a)(1); 493.1239(a) and
proficiency testing; General laboratory sys- (b)
tems assessment.
Comparison of test results:
§ 493.1709
§ 493.1709(a) .............................................. Comparison of test results ............................... § 493.1281(a)
§ 493.1709(b) .............................................. Evaluation of proficiency testing ...................... § 493.1236(c)(1)
Relationship of patient information to patient
test results:
§ 493.1711—Introductory text ..................... Comparison of test results; Analytic systems §§ 493.1281(b); 493.1289(a) and (b)
assessment.
§ 493.1711(a) .............................................. Comparison of test results ............................... § 493.1281(b)(1)
§ 493.1711(b) .............................................. Comparison of test results ............................... § 493.1281(b)(2)
§ 493.1711(c) ............................................... Comparison of test results ............................... § 493.1281(b)(3)
§ 493.1711(d) .............................................. Comparison of test results ............................... § 493.1281(b)(4)
§ 493.1711(e) .............................................. Comparison of test results; Analytic systems §§ 493.1281(b)(5); 493.1289(a) and (b)
assessment.
Personnel assessment:
§ 493.1713 ................................................... Personnel competency assessment policies; §§ 493.1235; 493.1239(a) and (b)
General laboratory systems assessment.
Communications:
§ 493.1715 ................................................... Communications; General laboratory systems §§ 493.1234; 493.1239(a) and (b)
assessment.
Complaint investigations:
§ 493.1717 ................................................... Complaint investigations; General laboratory §§ 493.1233; 493.1239(a) and (b)
systems assessment.
Quality assurance review with staff:
§ 493.1719 ................................................... General laboratory systems assessment; §§ 493.1239(b) and (c); 493.1249(b) and (c);
Preanalytic systems assessment; Analytic 493.1289(b) and (c); 493.1299(b) and (c)
systems assessment; Postanalytic systems
assessment.
Quality assurance records:
§ 493.1721 ................................................... Retention requirements; General laboratory §§ 493.1105(a)(5) and (b); 493.1239(c);
systems assessment; Analytic systems as- 493.1249(c); 493.1289(c); 493.1299(c)
sessment.
IV. Analysis and Responses to Public Subpart J—Patient Test Management for specimen and/or how the test results are
Comments Moderate Complexity (Including the interpreted.
Subcategory), High Complexity, or Any Response: We agree with the
We received numerous comments on Combination of These Tests commenters. The requirement, formerly
the final rule with comment period at § 493.1105(f), requires the laboratory
published on February 28, 1992 in the Following publication of the final rule
to ensure that the requisition or test
Federal Register. These comments were with comment period, we received
authorization includes any additional
from State agencies, proficiency testing approximately 150 comments regarding
information relevant and necessary for
programs, professional organizations, subpart J. The comments were in
accurate and timely testing and result
the Clinical Laboratory Improvement response to the requirements for
reporting (for clarity, we are adding
Advisory Committee (CLIAC), specimen submission and handling; test
‘‘interpretation’’ if applicable to this
laboratories, physicians, and the general requisition including oral requests and requirement). The requirement, now at
authorized persons; and test records and § 493.1241(c)(3), specifies that the
public. Summaries of the public
test reports, including confidentiality laboratory must request the patient’s sex
comments received and our responses to
and referral of specimens. The majority and age or date of birth as normal values
those comments are set forth below.
of the commenters disagreed with some and interpretation of test results are
Subpart I—Proficiency Testing portion of the requirements and some often dependent on this information.
Programs for Tests of Moderate commenters requested clarification of Concurrently, we are redesignating age
Complexity (Including the Subcategory), certain requirements while others or date of birth requirements, formerly
High Complexity, or Any Combination offered specific revised language. at § 493.1105(e), for Pap smear
of These Tests Specific comments received and requisitions to test requests (now at
responses to comments regarding § 493.1241(c)(3)). The time of specimen
We received a number of comments subpart J are set forth below. collection must also be requested when
on the topic of proficiency testing. We Comment: A number of State agencies it is relevant for the testing to be
intend to publish a notice of proposed disagreed with our removal of the performed. For example, this
rulemaking addressing proficiency requirement that laboratories comply information is important when
testing issues in more detail in the with applicable Federal, State, and local interpreting the results of peak and
future. We have, however, determined laws. trough therapeutic drug assays. In
that it would be appropriate to include Response: We agree with the addition, we are requiring that specimen
in this final rule a change that we commenters and are reinstating the source, when appropriate, be solicited
believe is necessary to improve the requirement now at § 493.1101(c). As on the test requisition. Specimen
operation of the CLIA proficiency part of the partnering relationship with handling, preservation, and preparation
testing program, related to the State agencies and local governments, (for example, use of proper transfer
percentage of required agreement among the reinstatement of this requirement media, inoculation of media in
participant or reference laboratories. will allow us to support a State or local microbiology and clinical cytogenetics,
Thus, we are addressing only one of the government that seeks to protect the and the application of appropriate
changes requested by the commenters public from actions it finds would be normal values reported with patient test
and recommended by the CLIAC. detrimental to public health. results) are dependent on the origin of
Specific comments received and Comment: Some commenters the specimen. Therefore, we are
response to comments regarding subpart disagreed with requiring written including specimen source, when
I are set forth below. authorization for oral test requests, appropriate, as part of the laboratory’s
describing the difficulties that this submission, handling, and referral
Comment: A few commenters, requirement causes.
professional organizations, and procedures (now at § 493.1242(a)(3)).
Response: We acknowledge that when We are also requiring specimen source
proficiency testing programs expressed a laboratory asks that an oral request for
their concerns over the change to a 90 to be included on the test report if
patient testing be followed with a warranted (now at § 493.1291(c)(5)).
percent consensus requirement to be written request, there is no guarantee
reached before a proficiency testing This routine laboratory practice was
that one will be received. On January inadvertently omitted from the final rule
sample could be graded. Commenters 19, 1993, we published a technical
felt there should be a grade assigned to with comment period.
correction in the Federal Register (58 Comment: One organization
their samples. One commenter stated FR 5215) and (58 FR 5229) that representing members of the laboratory
that their laboratory paid for samples, so amended the requirement formerly at community objected to the amount of
grading should be required. Proficiency § 493.1105. This requirement, now at information that a laboratory must have
testing programs had similar opinions. § 493.1241(b), states that oral requests on the test requisition, specifically the
The CLIAC recommended reducing the for laboratory tests are permitted only if information that is needed when
consensus required for grading the laboratory requests written or submitting a Pap smear. The
proficiency testing challenges to electronic authorization for testing organization stated that laboratories do
decrease the number of ungradeable within 30 days of the oral request and not have access to patient records and
samples as ungraded proficiency testing documents the efforts made to obtain a are dependent on the authorized person
is not effective in assisting laboratories written or electronic authorization. ordering the test to provide this
in their quality assessment of test Comment: We received several information. The organization agreed
performance. comments recommending information the information was important but
Response: We agree with the the laboratory should solicit and obtain assumed we would prohibit testing if all
commenters and are changing the on the test requisition. Specifically, the information was not obtained by the
percentage of required agreement among commenters believe the age and sex of laboratory.
participant or referee laboratories to 80 the patient, time of specimen collection, Response: We agree with the
percent in the specialties and and the specimen source should be commenter that the information being
subspecialties where 90 percent included since they are pertinent to requested is important. Therefore, we
agreement was previously required. either how the laboratory processes the are retaining the test request
requirements formerly at § 493.1105, test on the test report. They believed on the test report may be manually
(now at § 493.1241(c)) as relevant that too much information would make written, generated by an electronic
information necessary for proper test the report crowded and confusing. system, maintained on microfilm, or any
performance and interpretation. The test Another comment received from a other means, provided it contains all of
requisition requirements do not prohibit professional organization acknowledged the information that was on the original
laboratories from performing the testing the benefit of this requirement, but test report. Therefore, we are deleting
if the requested information is missing. stated its application to cumulative the reference to ‘‘exact duplicate’’ that
Although we expect laboratories to reports causes disruption of data was contained in the former
obtain this information when possible, presentation and utility of the report § 493.1109(h), and amending the
the potential negative impact of the and, in some cases, the information language now at § 493.1291(j) to clarify
missing information on the test results cannot reasonably be included. that the laboratory must be able to
may be addressed or noted on the Response: We agree the name and retrieve a copy of the original report. We
report. address of the laboratory performing the are also making a conforming change in
Comment: One State health test is an essential piece of information the retention requirement for test
department requested modification of that must be included on the test report. reports (now at § 493.1105(a)(6)).
the requirement for recording the time It provides a contact for the individual Comment: Many commenters stated
of specimen receipt into the laboratory, who requested or is using the test that the removal of the subpart on
stating we should require the time of results when additional information is laboratory information systems (LIS)
receipt only if it is pertinent to sample needed for result interpretation and was inappropriate and not logical
integrity, test method, or procedure. patient care. If a laboratory determines considering the current and future
Response: We disagree with the its reports are crowded or confusing, it direction of collection and
commenter. Recording the date and time has complete latitude and responsibility dissemination of laboratory data. Other
of specimen receipt enables the to reorganize the report in a manner that commenters indicated that the current
laboratory to determine the elapsed time will correct the problem as specified method of reporting patient results and
between specimen receipt and reporting formerly at § 493.1703 (now at the laboratory computer system was
of patient test results. It also provides a § 493.1299). A laboratory that generates overlooked.
mechanism to monitor transportation cumulative reports may use a single Response: We agree with all of the
times for specimens referred to the character identifier (for example, an commenters and are addressing some of
laboratory. Therefore, we are retaining asterisk or subscript) to identify a the commenters’ concerns pertaining to
this requirement formerly at particular reference laboratory that electronic patient and testing
§ 493.1107(b) (now at § 493.1242(b)). performed the test. This information information by doing the following:
Comment: One commenter stated the (the name and address of the reference • Adding a requirement at
final rule with comment period did not laboratory) may be defined on a § 493.1101(e) for laboratories to store
require a person’s name or unique subsequent page or on the back of the and maintain records in a manner that
identifier on the test report. report. Laboratories may develop other ensures proper preservation. Proper
Response: We agree with the formats to meet this requirement. storage of patient records that are
commenter that the final rule with However, we are retaining the collected in a LIS is essential for record
comment period did not specifically requirement formerly at § 493.1109(b) preservation and accurate recall of
require a patient’s name or unique (now at § 493.1291(c)(2)) to include the patient information. Without proper
identifier as part of the test report name and address of the laboratory storage and maintenance of records, the
formerly at § 493.1109. Therefore, we where the test was performed. timeframes, identification, and the
are adding at § 493.1291(c)(1), a Comment: One commenter questioned accessibility of records will not be
requirement for the laboratory report to the appropriateness of maintaining test possible.
include the patient’s name with an records in the patient’s chart or medical • Incorporating a requirement at
identification number, or a unique record. § 493.1241(e) for laboratories using LIS
patient identifier and identification Response: The CLIA regulation does to ensure that the requisition
number to ensure positive patient not preclude laboratories from storing information is accurately transcribed or
identification. The patient’s name alone test records in a patient’s chart or entered. The laboratory may establish its
is not a unique identifier, and when medical record; however, records must own mechanism to meet this
used on the test report, the patient’s include the following: requirement, possibly through random
name must be accompanied by an • Test analysis (including instrument checks or representative sampling of LIS
identification or accession number. printouts, if applicable). patient testing information verified
When a patient’s name is not used for • Identity of the personnel against that submitted on the original
confidentiality purposes, or when the performing the test. test request.
identity of the person is not known, a To retain this type of information in • Adding a requirement at
unique patient identifier must be a patient’s chart or medical record may § 493.1291(a) that requires laboratories
submitted with the specimen. The be cumbersome and impractical for QA to ensure patient test results are
laboratory must also use an activities; however, it is at the discretion accurately and reliably sent from the
identification number. In reviewing the of the laboratory. point of data entry to the final report’s
report requirements formerly at Comment: One commenter questioned destination in a timely manner. We are
§ 493.1109(b), interpretation was whether computer records of reports are providing frequently encountered
omitted. Therefore, we are adding acceptable in lieu of paper files. reporting scenarios that must be
interpretation to the test report Response: The requirement formerly reviewed by the laboratory to ensure the
requirements at § 493.1291(c)(6) for at § 493.1109(h) specifies that all test accuracy and reliability of the
those test results that require reports or an exact duplicate of each test transmitted patient result information.
supplemental information. report must be maintained by the • Requiring at § 493.1291(c) that the
Comment: Some commenters laboratory in a manner that permits date of the test report be identified on
disagreed with requiring the name and ready identification and timely the report. This date must be
address of the laboratory performing the accessibility. The information contained maintained as the date testing results
were generated as a final report and immunohematology and blood and changes in this final rule are based on
must not change on copies reported at blood products formerly at § 493.1107 the advice and comments we received.
a later date. introductory text and § 493.1221 (now at Specific comments and response to
The above requirements are intended § 493.1105(a)(3)(ii)) and formerly at comments regarding subpart K are set
to respond in part to the commenters’ § 493.1109 introductory text (now at forth below.
requests. We intend to publish, at a later § 493.1105(a)(6)(i)) to ensure Comment: We received mixed
date, a rule specific to laboratory consistency with the FDA requirements comments concerning the general QC
information systems. For example, for these types of records. requirements. Some commenters felt the
requirements for the establishment and QC requirements were burdensome and
verification of system programs, system Subpart K—Quality Control for Tests of would increase the cost of testing and
security, system and device Moderate Complexity (Including the asked that these requirements be deleted
maintenance, system operator functions Subcategory), High Complexity, or Any or revised. Conversely, some
and responsibilities, and system Combination of These Tests commenters agreed with the
backups. In the final rule with comment period, requirements, indicating that QC is
Comment: One commenter was the QC rules are located in subpart K absolutely essential to producing
concerned about limited record storage and include the general QC accurate test results and is good
space on-site and asked if off-site requirements and specific QC laboratory practice. Others stated the
storage of records would be acceptable requirements for each specialty and requirements of subpart K were both
provided the laboratory was able to subspecialty of testing. A phase-in reasonable and attainable. A few
produce these records during an period provided less stringent general commenters requested further
inspection. QC requirements for unmodified clarification.
Response: Records may be stored at a moderate complexity tests approved by Response: We agree with the
place of the laboratory’s choosing the FDA through the premarket comments that QC procedures are
providing the storage is appropriate and notification 510(k) or premarket essential to good laboratory practice and
the laboratory can produce the approval (PMA) process.
production of accurate test results.
documents within a reasonable time Control procedures verify that the
during the course of an inspection as Following publication of the final rule patient results are substantially
required at § 493.1773(c). with comment period, we received unaffected by day-to-day variation
Comment: Several commenters approximately 1,030 comments. Of caused by the test system, environment,
disagreed with the requirement to retain these comments, 280 were directed at or operator. While the requirement for
records for a minimum of 2 years or 5 the general QC requirements, 67 implementing QC may initially increase
years, depending upon the type of pertained to the specialty and the cost of testing in some settings, it
record. A professional organization subspecialty QC requirements, and may decrease the long term cost as
questioned whether instrument approximately 680 pertained to cytology improved accuracy and reliability of
printouts must be retained for 2 years if and histopathology requirements. The testing reduces the need for retesting
appropriate data are saved in a majority of the comments disagreed and unnecessary procedures or
retrievable manner. Other commenters with some portion of the requirements, treatments.
felt that 3 months, and, in one case, 6 indicating that the final rule with Comment: A manufacturer’s
months, would be sufficient time to comment period was either too organization requested that
retain instrument printouts. restrictive or too lenient. Some § 493.1202(c) be revised to include those
Response: We believe all records commenters requested clarification of products not subject to the FDA
related to testing, for example, records certain requirements, while others clearance process to allow laboratories
of test requests, patient test records offered specific revised language. A few performing these tests to meet the
including, if applicable, instrument comments agreed with the final rule phase-in QC requirements.
printouts, and copies of test reports are with comment period, while others Response: We agree that the
essential for the ongoing QA reviews indicated the requirements had either regulation needs to be revised to include
performed by the laboratory. Instrument been misinterpreted or misread. We these products, and provisions
printouts are test records and are addressed some of the commenters’ addressing these products were added
sometimes used as test reports and for issues in a technical correction in the revisions to the regulations
these reasons must be retained for the published on January 19, 1993 in the published in the January 19, 1993
appropriate length of time unless all Federal Register (58 FR 5215). technical corrections (58 FR 5215).
information is duplicated in another In evaluating the comments and Since these products are not evaluated
record system. Additionally, CLIA considering the types of revisions to by the FDA, they could not be included
requires biennial certification that make in this subpart, we obtained under § 493.1202(c) but were added to
includes an inspection of the recommendations from the CLIAC and § 493.1202(b) and subject to all
laboratory’s activities for compliance consulted with various professional applicable standards of subpart K.
with CLIA requirements by either an on- organizations and laboratory personnel. Comment: Comments were divided
site inspection of the laboratory or a In September 1996, we participated in concerning the phase-in of the general
self-assessment inspection through use public discussions at a 2-day meeting in QC requirements. Some commenters
of the Alternate Quality Assessment Atlanta, Georgia. At the public meeting, agreed with the phase-in while others
Survey (AQAS). These inspections manufacturers, laboratory organizations, were opposed. Some commenters felt
require a review of the testing and State representatives made that following manufacturers’
performed by the laboratory since the presentations concerning QC principles, instructions should be sufficient to meet
previous biennial inspection. Two years control materials and systems, the CLIA QC requirements. Others
is the minimum amount of time records manufacturers’ recommendations, costs expressed concern that FDA would not
must be retained to ensure that they are associated with control testing, and complete the review and approval of
available for review at inspection. personnel implications. Their manufacturers’ QC instructions by
However, we are clarifying the record recommendation was to make changes September 1, 1994. Most commenters
retention requirements for to accommodate new technology. Our opposed the phase-in provision. Some
commenters were concerned that providing some flexibility to the §§ 493.1211(b)(1) through
manufacturers’ QC protocols cleared by requirement formerly at § 493.1204(b) 493.1211(b)(13). Another commenter
the FDA might be less stringent than the (now at § 493.1101(d)) that requires suggested that laboratories be required
CLIA QC requirements. Other laboratories to post safety precautions. to retain each procedure’s original
commenters disagreed with having two The revisions now require that safety specifications and instructions for use
sets of general QC requirements, and procedures be accessible rather than as provided by the manufacturer, and
other commenters were confused about posted. maintain a list of any alterations or
the phase-in requirements and Comment: We received several changes in the procedure manual.
requested clarification. comments concerning the requirements Response: We disagree with the
Response: We implemented a phase- at § 493.1205. Most commenters commenter who requested that the
in of the general QC requirements to opposed the requirement prohibiting the procedure manual requirements be
allow previously unregulated use of expired reagents. One commenter deleted. All laboratories must maintain
laboratories performing only FDA- requested clarification of and follow procedure manual
approved or cleared, unmodified, and § 493.1205(c)(1) that requires the instructions in order to provide uniform
moderate complexity testing sufficient laboratory to define criteria for reagent patient testing. Therefore, we are
time to implement effective QC and specimen storage conditions. retaining the requirements for a
programs. During the phase-in, the FDA Response: We understand the procedure manual now at § 493.1251.
was to establish a process to review and concerns expressed regarding the use of Laboratories may use the manufacturer’s
clear manufacturers’ QC instructions for rare and expensive reagents and test system instructions to meet many of
CLIA QC purposes. Under this process, materials beyond their expiration dates. the procedure manual requirements, but
laboratories could meet certain CLIA QC However, the manufacturer has the must supplement them with any
requirements by following the FDA- responsibility for establishing expiration laboratory-specific information related
approved manufacturers’ QC dates that ensure the reagents and to its testing and reporting practices.
instructions. On four occasions, we materials will perform properly when Examples are the laboratory’s
extended the phase-in of the general QC used for patient testing. In addition, any procedures for reporting patient test
requirements that are currently in effect changes in the labeling of in-vitro results, including panic values or alert
until December 31, 2002. However, diagnostics must comply with Food, values, corrective actions to follow
because the CLIA program is user fee Drug, and Cosmetic Act requirements. when test systems become inoperable,
funded, we decided it would be prudent Therefore, we are not making any and criteria for specimen referral. The
to wait until the phase-in period ended revisions to the requirement formerly at use of the manufacturer’s test system
before implementing the FDA QC § 493.1205(e)(1) (now at § 493.1252(d)) instructions to meet many of the
review. This afforded us the survey prohibiting the use of expired reagents procedure manual requirements is
experience necessary to determine and other materials. permitted to ensure that laboratories
whether an additional FDA review In regard to licensed biological and follow the manufacturer’s instructions
would be of benefit to laboratories. We blood products, any exceptions to for patient testing and to minimize the
realized through our experience dating requirements must be granted by burden on laboratories in developing
inspecting laboratories that an the FDA in the form of an amendment procedure manuals.
additional FDA review would not be of to the product license. In this final rule, For clarity and consistency, we are
such benefit. Therefore, in this final we are consolidating all requirements reiterating the requirements formerly at
rule, we are eliminating the phase-in pertaining to the immunohematological §§ 493.1103(a) and 493.1211(b)(14) (now
requirements and establishing minimum testing and distribution of blood and at §§ 493.1242 and 493.1251) that the
general quality system requirements blood products (now at § 493.1271(b)). laboratory have written policies and
applicable to all nonwaived testing, We are adding language to the procedures for specimen submission. In
regardless of complexity. In addition, requirement formerly at § 493.1205(c)(1) addition, we included language now at
we are removing all references to the to clarify how the laboratory establishes § 493.1251(b)(13) to clarify the use of
FDA QC clearance process that was not and uses its criteria for storing reagents laboratory information systems for
implemented. However, we agree with and patient specimens. The requirement entering patient test results.
the commenters that it is essential for now at § 493.1252(b), states that the In addition, we agree with the
laboratories to perform testing according laboratory must define criteria for those commenter that laboratories must have
to the manufacturers’ test system conditions in the manufacturer’s test copies of test procedures. Therefore, we
instructions as required formerly at system instructions, when available, are retaining the requirement now at
§ 493.1202(c)(1) (now at § 493.1252(a)). that are essential for proper storage of § 493.1251(e) that laboratories must
Comment: A few comments were reagents and specimens, and accurate maintain a copy of the procedure with
received in response to the and reliable test system operation and the dates of initial use and
environmental and safety requirements test result reporting. The criteria must discontinuance for 2 years after a
at § 493.1204. Some commenters be consistent with the manufacturers’ procedure is no longer used.
indicated that the requirements were too instructions, if provided. These Comment: Several commenters
lenient. Others were opposed to conditions must be monitored, opposed the requirement at § 493.1211
exempting moderate complexity testing documented, and include (1) water for the director to approve, date, and
from the requirements at § 493.1204 quality; (2) temperature; (3) humidity; sign the procedure manual, approve any
during the phase-in, stating that all and (4) electrical tolerances. change in procedure, or re-approve the
laboratories should be subject to these Comment: One commenter agreed manual should there be a change in
requirements. with the requirements at § 493.1211, directorship. One commenter suggested
Response: We agree with the Procedure manual. Another commenter that the requirement be revised to state
commenters and therefore are retaining suggested that the procedure manual each procedure must be approved by the
the requirement formerly at § 493.1204 requirements be deleted. Two director before patient testing.
(now at § 493.1101, subpart J) and commenters opposed permitting the use Response: The director is the
applying it to both moderate and high of the manufacturer’s package insert to individual ultimately responsible for the
complexity testing. In addition, we are satisfy the requirements at operation and administration of the
testing facility and is therefore and resources necessary to establish or approved by the FDA through either the
responsible for authorizing all testing verify performance specifications. premarket notification (510(k)) or
procedures and any alterations or However, these requirements ensure premarket approval (PMA) process for
revisions of these procedures. If a that the laboratory has either established in-vitro diagnostic use. This includes
change in directorship occurs, re- test system performance specifications test systems exempt from FDA
approval of the manuals by the new or verified that it can obtain the premarket clearance or approval.
director is necessary since he or she manufacturer’s performance Regulations do not have retroactive
assumes responsibility for all testing specifications in the laboratory’s effect. The CLIA requirement’s effective
procedures and any alterations or environment using the laboratory’s date became applicable to newly
revisions of the procedures. We agree testing personnel. In addition, regulated laboratories on September 1,
with the comment stating that each establishment or verification of 1992. Those laboratories that were
procedure should be approved by the performance specifications are integral subject to regulations prior to this
director before patient testing. to the laboratory’s establishment of September 1, 1992 effective date were
Therefore, we are revising the appropriate and effective QC and already required to validate test
requirement formerly at § 493.1211(d) calibration protocols. These protocols procedures under former Federal
(now at § 493.1251(d)) to specify that must include descriptions of the regulations before the CLIA
the director reviews each procedure and numbers, types, and concentrations of requirements were implemented. This
change in procedure before use. We are all calibration and control materials, as rule does not have a retroactive effect.
also emphasizing that we do not expect well as the performance intervals. Laboratories performing unmodified
laboratories to suspend testing for those Calibration and control protocols based moderate complexity tests cleared or
procedures already in use that may not on unverified performance approved by the FDA are not required
have been approved before patient specifications could result in poorly to retroactively verify the
testing. However, effective April 24, controlled and inaccurate testing. In the manufacturer’s performance
2003, all alterations in current interest of establishing appropriate specifications. The results of the
procedures and all newly implemented calibration and control practices and laboratory’s control procedures,
procedures must be reviewed and improving the reliability, accuracy, and proficiency testing (required under
signed by the director before use. usefulness of patient testing, we are subpart H) and assessment activities are
In addition, we are revising the retaining the requirements formerly at used to verify test performance.
requirement formerly at § 493.1211(e) § 493.1213, and are now applying them However, as of April 24, 2003,
(now at § 493.1251(d)) to include the to nonwaived testing at § 493.1253. laboratories must, before testing, either
provision that requires procedures to be Laboratories employing methods (not verify or establish performance
re-approved if the directorship changes. modified by the laboratory) that have specifications for any new test system.
Section 493.1251(d) now states, manufacturer-established performance Comment: Some commenters
‘‘procedures and changes in procedures specifications must demonstrate before expressed approval of the requirements
must be approved, signed, and dated by reporting patient test results that they for the establishment and verification of
the current laboratory director before can obtain performance specifications a test system’s method performance
use.’’ If the directorship changes, the for accuracy, precision, and reportable specifications before its use, and
current director would not be expected range of test results for the test system, maintaining records of this activity
to suspend testing to review the comparable to those established by the while the test system is used for patient
procedures in use or changes to manufacturer. The laboratory director testing.
procedures approved by the previous must decide the extent to which these Response: We accept these positive
director. However, the current director performance specifications are verified comments and are retaining the
must review all procedures in use by the based on the method, testing conditions, requirements for the establishment and
laboratory in a timely manner. and personnel performing the test. verification of method performance
Comment: Approximately one third of In addition, we are clarifying when a specifications formerly at § 493.1213
the comments received disagreed with laboratory must establish test system (now at § 493.1253). However, we
§ 493.1213, Establishment and performance specifications (for realize the QC record retention
verification of method performance example, laboratories using a test requirements formerly at § 493.1221
specifications. Some individuals system in which the manufacturer does may have been misinterpreted as
opposed verifying the manufacturer’s not provide performance specifications) permitting the laboratory to discard
performance specifications for those now at § 493.1253(b)(2). Laboratories method performance specification
methods cleared by FDA as meeting must, before reporting patient test records after a 2-year period even
certain CLIA requirements for QC. One results, establish, as applicable, though the method may have continued
commenter disagreed with the performance specifications for the to be used beyond this timeframe.
requirement to establish performance following performance characteristics: Therefore, the analytic systems record
specifications for those methods (1) Accuracy; (2) precision; (3) retention requirement formerly at
developed in-house, modified by the analytical sensitivity; (4) analytical § 493.1221 (now at § 493.1105(a)(3)(i))
laboratory, or not cleared by FDA as specificity, including interfering specifies that records of the laboratory’s
meeting certain CLIA QC requirements. substances; (5) reportable range of test establishment and verification of
Another individual suggested that the results for the test system; (6) reference method performance specifications
standard be retroactive and apply to all intervals (normal ranges); and (7) any must be retained for the period of time
test methods. One commenter asked that other performance characteristic the test system is in use by the
this standard be revised to state, ‘‘The required for test performance. laboratory, but not less than 2 years. In
provisions of this section are not Section 493.1253(b)(1) uses the term addition, we are revising the original QC
retroactive for previously unregulated ‘‘FDA-cleared or approved test system’’ record retention requirement to
laboratories. Previously unregulated as defined (at § 493.2, Definition) in the accommodate the reorganization of the
laboratories are not required * * *.’’ November 9, 1997 revisions to the Food, regulation and clarify its intent.
Response: We understand the Drug and Cosmetic Act (Pub. L. 105– Comment: A few commenters
commenters’ concerns about the time 115), to mean a test system cleared or disagreed in general with the
requirements at § 493.1215, Equipment buffers and gases used to calibrate the We believe this is the maximum interval
maintenance and function checks. Other instruments are not like patient samples allowable for verifying accuracy and
commenters requested clarification. One and cannot be assayed in the same stability. In addition, we are
commenter felt that the requirements manner as patient samples. emphasizing that these regulations set
were too stringent, and another offered Response: We agree with the forth minimal requirements. In
specific language for revision. One commenters and are specifying in this establishing or verifying performance
commenter felt CMS, not the final rule that effective, April 24, 2003, specifications as required at § 493.1253,
manufacturer, should establish the calibration and calibration verification the laboratory may find it necessary to
frequency for performing function requirements (now at § 493.1255) will calibrate or verify calibration more
checks. apply to all nonwaived testing. frequently or to use more calibration
Response: Equipment maintenance To respond to the commenters’ materials than required at § 493.1255.
and function checks are necessary to concerns that the calibration and In response to the comment
ensure accurate and reliable test calibration verification requirements are concerning the inability of testing
performance. We are relocating the unclear, we are making some minor calibration materials (buffers and gases)
requirement formerly at § 493.1215 revisions in language for clarification in the same manner as patient
(now at § 493.1254) and renaming it purposes and removing duplicate specimens when verifying the
Maintenance and function checks. requirements. For example, the calibration of blood gas assays, we are
Laboratories using unmodified definitions of calibration and calibration retaining the additional requirements
manufacturers’ equipment, instruments, verification and reportable range are for routine chemistry formerly at
or test systems must perform being slightly modified (now at § 493.2). § 493.1245 (now at § 493.1267) that
maintenance and function checks as We are also removing the requirement supersede the general calibration and
defined by the manufacturer with at formerly at § 493.1217(b)(2)(ii)(B)(1) for calibration requirements at § 493.1255.
least the frequency specified by the laboratories to perform calibration Section 493.1267(a) specifically
manufacturer. Laboratories must also verification using calibration materials addresses calibration and calibration
document maintenance and function appropriate for the methodology and, if verification of blood gas analyses and
checks performed. We are adding possible, traceable to a reference method states the laboratory must calibrate or
language at § 493.1254(a)(2) requiring or reference material of known value to verify calibration according to the
that function checks be within the allow laboratories flexibility in choosing manufacturer’s specifications and with
manufacturer’s established limits before materials for calibration verification. at least the frequency recommended by
conducting patient testing. We are also In addition, we are retaining the the manufacturer. As long as the
retaining the present requirement (now requirement for laboratories, at a laboratory follows the manufacturer’s
at § 493.1254(b)) for laboratories to minimum, to perform calibration and calibration and calibration verification
establish protocols that ensure proper calibration verification procedures using instructions for the blood gas
test system performance, accurate and the manufacturers’ test system instrument, the CLIA requirements for
reliable test results and test reporting for instructions and the criteria verified or calibration and calibration verification
equipment, instruments, or test systems established by the laboratory formerly at are met.
developed in-house, commercially §§ 493.1217(b)(1) and 493.1217(b)(2) Comment: We received many
available but modified by the laboratory, (now at §§ 493.1255(a)(1), comments concerning various
or when protocols for maintenance and 493.1255(a)(2), 493.1255(b)(1) and components of § 493.1218, Control
function checks are not provided by the 493.1255(b)(2)). We are also retaining procedures. Some commenters misread
manufacturer. In addition, laboratories the requirement that calibration must be the CLIA regulation, and others offered
must document the maintenance and performed whenever calibration specific language for revision. Most
function checks performed. verification procedures are unacceptable commenters opposed testing two levels
Under this final rule, we are not and calibration verification be of control material each day of use. One
defining intervals for the performance of performed using a minimum of 3 values commenter indicated that the CLIA
maintenance or function checks because to verify the laboratory’s reportable requirements are burdensome and will
the manufacturer is better able to define range, at least once every 6 months or increase the cost of testing. Some
the appropriate procedures and whenever an event occurs as specified commenters expressed concern that the
intervals necessary to maintain and formerly at § 493.1217(b)(2)(ii)(C) (now requirements are arbitrary and do not
ensure proper equipment, instrument, at § 493.1255(b)(3)). recognize unit use test systems. Another
and test system performance. In response to the comment that the commenter asked if procedural controls
Comment: Several commenters frequency of calibration be mandated by may be used to satisfy the control
suggested that § 493.1217, calibration CMS, we are retaining the requirement requirements.
and calibration verification, or formerly at § 493.1217(b)(1) (now at Response: We appreciate the
substantially equivalent requirements, § 493.1255(a)) that requires laboratories commenters’ concerns about the
should also apply to FDA-approved or to calibrate according to the frequency and costs of performing
cleared, unmodified moderate manufacturer’s instructions, if provided, control testing. However, CLIA
complexity testing at § 493.1202(c). In and the laboratory’s specifications. We regulations will continue to describe the
addition, we received comments believe that laboratories should perform purpose of control procedures, that is, to
requesting clarification of § 493.1217. calibration at the interval specified by assess the accuracy and precision of test
One commenter stated that CMS, not the the manufacturer to ensure proper performance. The control procedures
manufacturer, should establish the instrument and test system must monitor the complete analytical
frequency of calibration. A performance. For calibration verification process by detecting immediate errors
manufacturer commented that a loose formerly at § 493.1217(b)(2) (now at (those that occur due to test system
interpretation of the calibration § 493.1255(b)), laboratories are to follow failure, adverse environmental
verification requirement to assay the manufacturer’s specifications and conditions or operator performance
calibration materials in the same the laboratory’s established protocols for problems) and monitor over time the
manner as patient samples is needed for calibration verification that must be accuracy and precision of test
certain blood gas analytes because performed at least once every 6 months. performance that can be influenced by
subtle changes in test system as documented in test system must be of different concentrations than
performance, environmental conditions, instructions approved by the FDA. the calibrators employed to set
and variance in operator performance Another commenter suggested that instrumentation. We recommend that
(for example, different operators and § 493.1218(a) be revised to state, ‘‘that the acceptable range of control materials
same operator variations in specimen the laboratory should run controls as reflect some clinical decision points,
handling and testing). specified by the manufacturer’s both normal and abnormal.
In response to the comments instructions.’’ Several commenters and Comment: One commenter suggested
concerning unit use test systems and the one organization stated it is the that § 493.1218(d) be revised to include
use of procedural controls, we are laboratory director’s responsibility to a provision that if the performance
making allowances for the use of design the control system needed to specifications at § 493.1213 are
procedural controls in Appendix C of achieve the desired quality. exceeded, the laboratory must take
the State Operations Manual (CMS Pub. Response: We consider the corrective action before patient testing
7) when equivalent quality procedures requirements established in subpart K as can continue.
can be demonstrated. the minimum control measures needed Response: We agree with the
In addition, we are providing a to ensure accurate and reliable test commenter. The requirements formerly
definition for test system (now at results. According to the requirements at § 493.1219(a) (now at
§ 493.2). A test system is the formerly at § 493.1213 (now at § 493.1282(b)(1)) require corrective
instructions and all of the § 493.1253), each laboratory must verify action, and the requirements formerly at
instrumentation, equipment, reagents, or establish a test system’s method § 493.1701 (now at § 493.1289(b))
and/or supplies needed to perform an performance specifications and use this require the laboratory to review the
assay or examination and generate test information in determining appropriate effectiveness of its corrective actions
results. calibration and control protocols. This and, if necessary, revise policies and
A control material must detect errors may include more frequent testing and procedures to prevent recurring
in the entire testing process. It must also greater numbers of materials than problems.
monitor the quality of the results specifically provided under CLIA Comment: One commenter disagreed
provided by the test system. It may be regulations. For example, the laboratory with the requirement to check each
supplied by the test system is required to perform calibration and batch or shipment of media.
manufacturer or another source. We are control procedures in the manner Response: The CLIA regulations allow
also relocating the requirement for necessary to ensure quality results. In laboratories to use the manufacturer’s
control materials to be tested in the cases where the manufacturer’s QC checks of certain media, provided
same manner as patient samples instructions require more stringent the manufacturer’s product insert
formerly at § 493.1218(c) (now at testing of calibrators, control materials, specifies that the manufacturer’s QC
§ 493.1256(d)(8)) and clarifying that this or both, the laboratory is required to checks meet the NCCLS standards for
requirement applies to control materials follow the manufacturer’s instructions. media QC formerly at § 493.1218(f)(4),
and that over time control testing must Therefore, we are clarifying that now addressed in Appendix C of the
be rotated among all operators who laboratories must follow the State Operations Manual (CMS Pub. 7).
perform the testing (now at manufacturer’s instructions for control For media not included by NCCLS, we
§ 493.1256(d)(7)). testing if they meet or exceed the believe it is critical that the laboratory
We are reducing the frequency of requirements now at § 493.1256(d)(3). check each batch of media to ensure that
testing control materials from ‘‘each We agree with the comment it is not contaminated, supports growth
run’’ to ‘‘each day of testing.’’ We are concerning the laboratory director’s of appropriate organisms, and elicits the
retaining the former requirements for responsibility to determine appropriate correct biochemical response(s). The
qualitative procedures (test positive and control procedures to monitor the former § 493.1218(f)(4) (now
negative control materials) and complete analytical process. This § 493.1256(e)(4)) clarifies that media
quantitative procedures (test two levels requirement is specified in CLIA checks must be performed before, or
of control material). For test procedures regulations under the director’s concurrent with, initial use of media.
producing graded or titered results, we responsibilities at § 493.1407(e)(5) for Comment: A few commenters
are relocating the requirement to test a moderate complexity testing and expressed disagreement with the
negative control and a control of graded § 493.1445(e)(5) for high complexity requirement to evaluate the detection
or titered reactivity from Syphilis testing. phase of direct antigen systems and the
serology and General immunology Comment: A commenter suggested extraction phase when it is included.
formerly at §§ 493.1239(b) and that acceptable control materials are two Response: We believe the laboratory
493.1241(a), respectively (now at samples of different concentrations of must verify that all steps of a testing
§ 493.1256(d)(3)(iii)). controls or two concentrations of procedure are functioning properly to
As part of updating the requirements calibration material of a different lot prevent erroneous results. Therefore, we
for new technology and test other than the lot used for assay are retaining the requirement formerly
methodologies formerly at calibration, or any combination that at § 493.1218(b)(4) (now at
§ 493.1218(b)(3) (now § 493.1256(d)(5)), results in both normal and abnormal § 493.1256(d)(3)(iv)) that requires
we are revising the wording of the values. laboratories to test two control
control requirement for electrophoresis Response: We agree with the materials, one that is capable of
procedures. commenter and emphasize that any detecting errors in the extraction phase.
Comment: One commenter urged that calibrator used as control material must Comment: One commenter agreed
we remove specific stipulations for be of a different lot number than the with requiring the determination of
frequencies of performing QC or one(s) used to establish a cutoff value or statistical parameters for each lot of
calibrations and substitute reference to calibrate the assay. Therefore, we are calibration or control materials.
an agency or professional association revising this requirement formerly at Response: We are retaining the
guidelines. The commenter also § 493.1218(b)(2)(now at requirement formerly at § 493.1218(d)(2)
recommended that we accept alternate § 493.1256(d)(9)) to clarify that the (now at § 493.1256(d)(10)(i)) for
approaches suggested by a manufacturer calibrators used as control materials laboratories to have statistical
parameters for each lot of control laboratories to have corrective action the responsibility of each laboratory to
material. In addition, we are clarifying policies and procedures that are ensure that the results it reports are
that the requirement applies to controls followed as necessary to maintain the accurate. Repeat testing is one method
with quantitative results. When laboratory’s operation for testing patient of verifying the test results. However, it
calibration materials (not used to specimens in a manner that ensures is up to each laboratory to determine the
establish a cutoff value or calibrate the accurate and reliable patient test results protocols it will follow to confirm the
test system) are used as control and reports. This includes policies test results that it reports.
materials, the laboratory must have governing the reporting of patient
Section 493.1223 Condition: Quality
statistical parameters for each lot of results that exceed the reportable range
Control-Specialties and Subspecialtes
calibration material. of the test system. The analytic
Comment: Some comments received for Tests of Moderate or High
assessment requirements at § 493.1289
were in reference to § 493.1219, Complexity, or Both
require the laboratory to monitor and
Remedial actions. One commenter evaluate the corrective actions taken Specific comments received and
requested clarification and another and revise policies and procedures as response to comments regarding
requested deletion of § 493.1219(a)(2) necessary to prevent recurrences of § 493.1223, specialty or subspecialty
that requires the laboratory to document problems. control requirements are set forth below.
all remedial action taken when patient Comment: One commenter suggested Comment: One commenter stated that
test results are outside of the that CLIA rules require all original the specialty and subspecialty QC
laboratory’s reportable range for the test worksheets and instrument printouts to requirements are too lenient.
system. One individual asked for be retained for 6 months, indicating that Response: The specialty and
clarification of § 493.1219(d)(3) that some laboratories destroy, delete, or subspecialty QC requirements are
requires the laboratory to maintain exact erase records of unacceptable QC in minimum requirements that reflect good
duplicates of both original and corrected order to avoid showing remedial action laboratory practice and must be
reports for 2 years when errors in the and reassessment of all patient tests followed by all laboratories performing
reported test results are detected. One results associated with the failure. nonwaived testing. However, based on
commenter suggested that no patient Response: We understand the the laboratory’s establishment and
results that are less than the lowest concerns expressed by the commenter. verification of its test systems’
calibrator or higher than the highest However, we believe the CLIA performance specifications (now at
calibrator can be reported unless they regulations adequately address § 493.1253), the laboratory may
are reported as less than or greater than documenting all control procedures determine that, to ensure accurate and
the lowest or highest calibrator or the performed formerly at § 493.1221 (now reliable test results, it must implement
patient specimen is diluted to determine at §§ 493.1256(g) and 493.1105(a)(3)), more stringent control procedures than
a higher value. maintaining records of all control the minimum requirements imposed. In
Response: The requirement formerly procedures performed formerly at addition, it is the laboratory director’s
at § 493.1219(a)(2) (now at § 493.1221 (now § 493.1105(a)(3)), responsibilities to ensure that the
§ 493.1282(b)(1)(ii)) requires assessing corrective actions taken laboratory has systems that ensure the
documentation of all remedial actions formerly at § 493.1705 (now at quality of the laboratory services
(now ‘‘corrective’’ actions) when patient §§ 493.1289(a) and (b)) and retention of provided and identify failures in quality
values are outside of the laboratory’s the original worksheets and instrument as they occur (§§ 493.1407(e)(5) and
reportable range of patient test results. printouts for a period of 2 years or more 493.1445(e)(5)).
The documentation can be an formerly at § 493.1107 (now at Comment: One commenter disagreed
instrument printout or other document § 493.1105(a)(3)). We also believe that if with § 493.1223 stating a laboratory
that reflects the problem, corrective the laboratory deletes or alters a control could lose approval to perform testing
action, and outcome. The laboratories result in any manner, it is expected that in an entire specialty or subspecialty if
must retain this information for the the laboratory will document the exact it is deficient in performing QC for a
required period and the corrective circumstances in which deletion or single test. The commenter urged that
actions themselves may be as alteration occurred and document all the language be changed to ‘‘Failure to
elementary as diluting and retesting the corrective actions taken to prevent satisfy requirements for an individual
specimen. We are not making any reoccurrence. test or analyte would result in loss of
revisions to this requirement. Comment: One commenter felt that approval for that test or analyte only.’’
The requirement formerly at there should be a requirement that any Response: We emphasize that CLIA
§ 493.1219(d)(3) (now at abnormal, life-threatening, or panic certification of laboratories is not
§ 493.1105(a)(6)) requires the laboratory value result obtained on a moderate granted on a test-by-test basis, but by
to maintain a copy of the original report, complexity test should be repeated by a specialty or subspecialty of testing.
or be able to retrieve a copy of the more accurate method of testing. Therefore, if a laboratory has significant
original report and the corrected report Response: The requirement formerly problems related to only one test or
for 2 years. Copies of test reports may at § 493.1109(f) (now at analyte in a specialty or subspecialty
be manually written, photocopies, § 493.1251(b)(13)) requires laboratories and the laboratory fails to correct those
electronically generated, or maintained to develop written procedures for problems, it could jeopardize its
on microfilm provided they contain all reporting life-threatening results (panic certification for the specialty or
of the information supplied on the or alert values). In addition, under the subspecialty area. For example, the
original test record or report. requirement formerly at § 493.1109(f) laboratory is notified in writing of the
We agree with the suggestion that (now § 493.1291(g)) laboratories must deficiencies found during a survey and
results outside of the reportable range of immediately alert the individual or is given an opportunity to correct the
the test system may not be reported entity that requested the test and, if deficiencies. If the laboratory does not
without corrective action or explanatory applicable, the individual responsible correct the deficiencies, sanctions could
remarks. Therefore, requirements for using the test results when any test be imposed as specified in Subpart R—
formerly at § 493.1219 (now at result indicates an imminently life- Enforcement Procedures. Therefore, we
§ 493.1282, Corrective actions) require threatening condition. In addition, it is are deleting the enforcement
information formerly at § 493.1223 for testing Salmonella and Shigella requirements for the reagents surveyed
because subpart R contains this antisera should be determined by the by ASM in the subspecialties of
information. In addition, revocation of periodicity supported by each bacteriology formerly at § 493.1227
specialty or subspecialty certification laboratory’s data. (now at § 493.1261) and mycology
for problems related to a particular test In making this presentation, ASM formerly at § 493.1231 (now at
would be taken only as a last resort. stated that the changes they were § 493.1263), except for requiring in
proposing would improve the cost bacteriology that the Gram stain be
Sections 493.1225 Condition: effectiveness of the CLIA program and tested each week of use, and antisera be
Microbiology; 493.1227 Condition: quality assurance programs in clinical tested when each batch, lot number, and
Bacteriology; 493.1229 Condition: laboratories without compromising shipment is prepared or opened, and
Mycobacteriology; 493.1231 public health. The CLIAC supported the once every 6 months thereafter. We are
Condition: Mycology; 493.1233 proposal and recommended the also requiring in mycology that the
Condition: Parasitology; and 493.1235 incorporation of these changes into the laboratory check each batch, lot number,
Condition: Virology CLIA regulations. and shipment of lactophenol cotton blue
Specific comments received and Response: We appreciate the efforts of when prepared or opened for intended
response to comments regarding ASM, and the data they provided. The reactivity with control organisms.
§§ 493.1225, 493.1227, 493.1229, survey results provided the supporting Additional control testing for
493.1231, 493.1233, and 493.1235 are information and data needed to revise lactophenol cotton blue is not required.
set forth below. the control testing frequency The required control testing frequencies
Comment: A professional requirements. Based on the low failure for other reagents and stains will default
organization, the American Society for rates for the commercial microbiology to the general control procedures
Microbiology (ASM), commented that reagents surveyed, we agree it is requirements formerly at § 493.1218(f)
the CLIA QC requirements should be adequate to test the majority of these (now at § 493.1256(e)(1) and (2)). The
revised over time as new information is reagents with each batch (prepared in- general control requirements for
made available about the performance house), lot number (commercially reagents include testing each batch
parameters of reagents or test systems. prepared), and shipment when prepared (prepared in-house), lot number
At a CLIAC meeting, this organization or opened for positive, negative, and (commercially prepared) and shipment
presented data on control failures for graded reactivity, as applicable. We also when prepared or opened. The general
commercial microbiology reagents and agree with checking antisera initially control requirements for stains (for
stains and suggested that the current and once every 6 months thereafter example, methylene blue) include
frequencies for control testing of a except for epidemiological testing that is testing staining materials for intended
number of microbiology tests or reagents not subject to CLIA. reactivity each day of use. As indicated
are excessive. ASM collected the data For two of the stains surveyed, the by ASM, we believe these changes will
via two surveys of 304 clinical Gram stain and methylene blue, we do decrease the cost of microbiology
microbiology laboratories that perform not agree that the low failure rate of the testing, without significantly affecting
varying levels of microbiological testing. reagents is sufficient reason to decrease the quality of the test results.
It included failure rates for a total of the stringency of the control The CLIAC requested further input
14,731 lots of reagents and stains, requirements. The Gram stain procedure from ASM on appropriate control
representing 21 different tests. Reagents uses several reagents and has multiple requirements for microbiology. ASM
and stains for 11 of the tests surveyed steps that require specific timing for submitted the following
currently have control testing accurate results. Also, interpretation of recommendations based on consultation
frequencies specified in the CLIA the stained smear requires individual with clinical microbiologists:
regulations: catalase, oxidase, coagulase skill and expertise. By decreasing the • The mycology requirement (for
plasma, Salmonella antisera, Shigella frequency of control testing for this auxanographic media for nitrate
antisera, Gram stain reagents, optochin, procedure to once every batch, lot assimilation) to check the nitrate reagent
bacitracin, CefinaseTm (beta lactamase), number, and shipment, small each day of use with a peptone control
X and V factor strips and disks, and laboratories that perform only rare Gram is not relevant since most laboratories
germ tube test. In this final rule, specific stains on direct specimens may not test no longer perform this test for fungal
control testing frequencies are not given controls for a period of months. We do identification. This requirement could
for eight reagents (spot indole, not believe this is appropriate for a be deleted, and if laboratories do use the
staphylococcal latex reagents, critical test used, in some cases, to procedure, it would be sufficient to
streptococcal latex grouping reagents, presumptively diagnose an infectious perform control testing with each batch
PYR disks, deoxycholate, KOH (fungal), disease (for example, direct smear for or lot.
LAP disks, and ALA) and two stains Neisseria gonorrhoeae). For this reason, • The requirement for parasitology
(lactophenol cotton blue and methylene we are maintaining the current weekly laboratories to check permanent stains,
blue). Based on the results of their control testing requirement for Gram each month of use, with a fecal sample
surveys, the ASM proposed that stain in addition to testing with each should be changed to ‘‘with a fecal
laboratories should only be required to new batch, lot number and shipment. sample or commercial QC slide.’’
test new lot numbers of those Similar to the Gram stain usage in • To control the decontamination
commercial microbiology reagents that small laboratories, methylene blue process for mycobacteriology culture
had a 98 percent or greater success rate stains may not be performed for an specimens, process a specimen
(all reagents they surveyed met this extended period of time, especially in containing Mycobacterium fortuitum
requirement). In addition to testing each laboratories that do not routinely use with each new lot number or batch of
new lot, ASM recommended that this staining procedure. We do not decontaminating agent.
laboratories test Salmonella and believe it is overly burdensome to • The frequency of control testing
Shigella antisera every 6 months require control testing of this stain each should be standardized for all
thereafter. ASM recommended that for day of use. microbiology subspecialties. Although
epidemiological testing conducted in In making the revisions discussed there has been no data collected for
public health laboratories, the frequency above, we deleted the specific control reagents or stains used in subspecialties
other than bacteriology, ASM suggested suggested for doing this is only one way for control procedures for all tests are
that it was their experience that these in which it may be accomplished. There now at § 493.1256(d). This provision
reagents and stains perform as well as are a number of other ways in which requires all laboratories to follow
the reagents surveyed for bacteriology. this process may be controlled (for manufacturer’s instructions for control
• Molecular amplification control example, monitoring the contamination testing, and to, at minimum, conduct a
procedures should adhere to standards rate over time to ensure the appropriate test that includes two control materials
outlined in the NCCLS document organisms are being killed). In an effort of different concentrations (a positive
‘‘Molecular Diagnostic Methods for to maintain flexibility in CLIA and negative control are required for
Infectious Diseases, MM3–A, 1995.’’ At regulations, in this final rule, we are not qualitative tests) on each day patient
a minimum, control procedures for adding this ASM proposed control specimens are tested. CLIA regulations
these tests should validate cell lysis, requirement to those for require that if the laboratory determines
absence of inhibitors, absence of mycobacteriology. As noted formerly at additional numbers or types of controls,
contamination, and adequate § 493.1103(a) (now at § 493.1232), the or a greater frequency of running
amplification. The following controls laboratory must establish and follow controls is needed to detect immediate
should be included with each run: written policies and procedures that error and monitor test performance over
• Positive control (low range of assay assure optimum integrity of patient time, the numbers, types, and or
sensitivity). specimens from the time they are frequency of controls must be increased
• One to five negative controls. collected until testing has been accordingly.
• Internal control. completed and results reported. In While we agree with the
• Quantitative assays should include addition, former § 493.1103(a) (now at recommendation made by ASM
two to three standards of known copy § 493.1242(a)(6)) requires laboratories to describing the positive and negative
number. For microbial genotyping, have and follow written policies and controls that should be used for
control procedures should include at procedures for specimen processing, molecular amplification procedures, the
least two isolates of the same species and former § 493.1703 (now at CLIA control requirements are
being tested. One isolate should have §§ 493.1249(a) and (b)) requires the minimum requirements and do not
the same phenotype as the unknown, monitoring and assessment of these specify that a positive control must be
and one should be a different policies and procedures, and the at the low range of assay sensitivity, or
phenotype. implementation of corrective actions to that more than one negative control be
Response: Our responses to the above resolve problems that are identified. tested daily. Likewise, these minimum
recommendations are set forth below. These requirements ensure that the requirements do not specify the types of
We agree that the mycology processing of mycobacterial specimens controls that must be included with
requirement for control testing of nitrate is monitored, assessed, and controlled, microbial genotyping, but only that two
assimilation on auxanographic media is while allowing the laboratory to use any controls must be tested each day patient
not relevant for the large majority of of several acceptable methods to do so. specimens are tested.
laboratories performing fungal We agree with ASM that, whenever However, if test system instructions
identification, and have deleted that possible, the frequency for control specify such control testing, or if the
requirement. If laboratories use the testing should be standardized for all laboratory determines (during its initial
procedure, they will be required, as microbiology subspecialties. evaluation of the test system at
stated formerly at § 493.1218(f) (now at Frequencies for individual reagents and § 493.1253) that more controls are
§ 493.1256(e)(1)) to test the medium and stains are not specified in CLIA needed, the additional control testing
reagents with each batch (prepared in- regulation for mycology and virology. must be performed.
house), lot number (commercially For parasitology, a frequency For molecular amplification
prepared), and shipment when prepared requirement (to test once a month) is procedures, ASM also recommended the
or opened. This will be the same control only given for permanent stains. The inclusion of an internal control in each
testing as required for other reagents frequency requirement for all other run, primarily to detect inhibition of the
and media used for fungal identification reagents and stains in these amplification process. We agree that for
procedures. subspecialties is the default contained some amplification procedures the
The language formerly at in the general control procedure presence of inhibitors or interfering
§ 493.1233(c) (now at § 493.1264(c)) requirements that are now at substances in certain specimens may
requires laboratories to check § 493.1256(e)(1) and (2). cause false negative test results, and that
permanent stains each month of use by We agree appropriate requirements for for these procedures, a control system is
using a fecal sample control. This molecular amplification procedures are necessary to detect inhibition. However,
terminology does not preclude the use needed, and that the NCCLS standards as noted by NCCLS, inhibitors are not a
of a fecal sample as a control or a are an excellent reference for significant source of false negative
commercially prepared control slide. laboratories to use. Requirements results for every test, and if inhibitors or
The requirement remains as written in addressing most of the interfering substances are encountered
existing CLIA regulations; however, we recommendations made by ASM for only rarely, NCCLS does not
will note this clarification in Appendix amplification procedures are included recommend running controls for
C of the State Operations Manual (CMS in CLIA regulations, although not as inhibition. Therefore, we have added a
Pub. 7). specifically as suggested by this requirement at § 493.1256(d)(3)(v) that
We recognize ASM’s concern that the organization. CLIA regulations require states, if reaction inhibition is a
mycobacteriology decontamination the laboratory director to have control significant source of false negative
process be monitored and adequately procedures to monitor the complete results, the laboratory must include a
controlled to ensure that the analytic process. For amplification control system to detect such inhibition.
decontaminating agent is of the proper procedures this includes, in general, In response to the ASM
strength to kill contaminating organisms validating cell lysis and ensuring recommendation that quantitative
without destroying mycobacteria absence of inhibitors, absence of assays include two to three standards of
(especially Mycobacterium contamination, and adequate known copy number, as stated above,
tuberculosis). However, the method they amplification. The CLIA requirements under CLIA regulations, quantitative
tests must include at least two control inoculated and read manually, and graded for reactivity. We are retaining
materials of different concentrations per those that are part of an automated the control procedures requirements for
day. Standards may be used in lieu of instrument system. We are retaining the qualitative test systems formerly at
control materials, as long as they are not requirement formerly at § 493.1218(f)(1) § 493.1218(b)(1) (now at
the same as the materials used to (now at § 493.1256(e)(1)) that § 493.1256(d)(3)(ii)).
calibrate the test system or establish a laboratories check each batch (prepared Comment: One commenter
cutoff. in-house), lot number (commercially recommended we add ‘‘XV discs or
In reviewing the CLIA regulations prepared), shipment of reagents, disks, strips’’ to § 493.1227(a)(2) that requires
concerning control procedures and QA stains, antisera, and identification testing both positive and negative
requirements for molecular systems (systems using two or more control organisms each week of use, and
amplification procedures, the CLIAC substrates and/or reagents) when delete § 493.1227(b) that requires testing
discussed appropriate control prepared or opened for positive and the XV discs or strips with only a
procedures and QA for genetic testing negative reactivity. We do not believe positive control organism each week of
(September 16, 1998 through September additional testing of these systems is use.
17, 1998). CLIAC recommended that needed if they are stored and Response: Testing of XV discs or
controls for genetic testing should be maintained under appropriate strips was limited to only a positive
considered for laboratories in general, conditions. Further testing is only control each week of use because there
including ensuring that adequate necessary if labile reagents must be is no known available control to check
controls are in place to minimize prepared or used each time the kit is negative reactivity for the group of
contamination. This is especially used or if specified by the manufacturer. organisms that this test identifies. We
important when performing molecular Comment: Several commenters are deleting the specific QC
amplification procedures. To ensure the requested clarification of the control requirements for testing X, V, and XV
control of contamination, we have requirement at § 493.1218(b)(1) for disks or strips. These disks or strips are
amended the requirements for facilities, qualitative tests as applied to now subject to the general control
formerly at § 493.1204(a) (now at microbiology procedures. The procedure requirements formerly at
§ 493.1101(a)) to require laboratories to commenters asked which of the § 493.1218(f)(1) (now at
be constructed, arranged, and biochemical tests or media used for § 493.1256(e)(1)) that include testing
maintained to minimize contamination microbial identification would be each new batch (prepared in-house), lot
of patient specimens, equipment, considered qualitative tests. number (commercially prepared), and
instruments, reagents, materials, and Response: Biochemical tests using shipment when prepared or opened for
supplies. A uni-directional workflow specific reagents or growth tests that positive and negative reactivity. Since
must be maintained for molecular employ selective or differential media there is no control available to check
amplification procedures not contained (for example, indole tests, citrate media) negative reactivity for XV disks or
in closed systems. This must include that are a part of the total system of strips, the use of only a positive control
physically separate areas for specimen identification from culture are not for XV disks or strips will be deemed to
preparation, amplification and product considered qualitative tests in meet the CLIA regulation as specified in
detection and, as applicable, reagent microbiology. Therefore, we are Appendix C of the State Operations
preparation. We believe these measures retaining the requirement formerly at Manual (CMS Pub. 7).
will decrease the potential for § 493.1218(f)(1) (now at Comment: Several commenters
contamination to the extent possible in § 493.1256(e)(1)) that states laboratories recommended we change the control
a clinical laboratory. must check each new batch (prepared requirement for daily testing of
Comment: Several commenters in-house), lot number (commercially antimicrobial susceptibility procedures
requested clarification of the control prepared), and shipment when prepared to a weekly requirement, as specified by
requirements for kit systems used for or opened for positive, negative, and NCCLS. One commenter also suggested
bacterial and fungal identification. One graded reactivity, if applicable. manufacturers develop control
commenter specifically requested the Specifically, former § 493.1218(f)(4) procedures consistent with NCCLS
addition of a provision at § 493.1231, (now at § 493.1256(e)(1) and (4)) antimicrobial susceptibility testing
Mycology, that would require the testing requires each batch of media to be standards whenever feasible.
of each new shipment of test kits or checked before or concurrent with Response: CLIA requires daily control
strips used for organism identification initial use for sterility, and its ability to checks for antimicrobial susceptibility
with organisms giving positive and support, select, or inhibit growth, as testing, formerly at § 493.1227(c)(2)
negative reactions for each test before or intended, and/or provide the (now at § 493.1261(b)(1)) unless CMS
concurrent with testing of clinical appropriate biochemical response. The approves a procedure that provides
isolates. Another commenter questioned manufacturer’s control checks of media equivalent quality testing as specified in
whether these systems would be subject may be used if the product insert Appendix C of the State Operations
to the requirement described at specifies they meet the NCCLS Manual (CMS Pub. 7). In this case, the
§ 493.1202(c)(4) to test at least two standards for media control testing. procedure providing equivalent quality
levels of control materials each day of These individual procedures do not testing is the NCCLS standard allowing
testing. require control checks with each run of the laboratory to perform weekly control
Response: We agree with the patient specimens or further testing testing of antimicrobial susceptibility
commenter that in mycology, or any unless specified by the manufacturer or procedures after establishing accuracy
other subspecialty area of microbiology, under specialty or subspecialty control control limits through initial daily
new shipments of test kits or strips used requirements. Biochemical tests or testing. The laboratory may continue
for organism identification should be media that provide microbial performing weekly control testing
tested with organisms giving positive identification from a direct specimen or provided the control results do not
and negative reactions for each test culture (for example, direct antigen tests exceed the established limits.
before or concurrent with initial testing for group A streptococcus, bacterial Comment: One commenter requested
of clinical isolates. This includes serotyping from culture) are considered clarification of the control requirements
identification kits or panels that are qualitative microbiology tests and are for antimicrobial susceptibility testing
with regard to the frequency of testing it is important for laboratories to requirement as provided at § 493.1256
the disks, media, and overall procedure. accurately identify individual species as an alternative procedure in Appendix
The commenter felt that there is a within this genus. This results in C of the State Operations Manual (CMS
contradiction between §§ 493.1227(c) increasing numbers and types of Pub. 7).
and (c)(2) and that one of these identification procedures being Comment: One commenter stated
statements should be deleted. performed and it is critical that the positive and negative reactivity should
Response: In the former regulation, accuracy of each of these tests be be checked each day of use for all acid-
antimicrobial susceptibility testing verified each day of use. This can best fast staining procedures, rather than
requires that whenever a new batch of be ensured each day of use by including each week of use.
media or a new lot number and both an acid-fast control organism that Response: We agree with the
shipment of antimicrobial agents (disks) produces a positive reaction and an commenter that both fluorochrome and
are put into use, the laboratory must acid-fast control organism that produces conventional acid-fast stains should be
verify that the media and agents perform a negative reaction for each test. We are tested more frequently than each week
within acceptable control parameters for revising the requirement formerly at of use and that both positive and
testing. Following this initial § 493.1229(a) (now at § 493.1262(a)) to negative control organisms should be
verification that the test components reflect this change. tested. Nonpathogenic mycobacteria in
(that is, media and antimicrobial agents) Comment: One commenter expressed water supplies have been found to
are working appropriately, the test concerns regarding the expense of contaminate buffers, rinse water, or
procedure must be checked routinely testing controls and stated that the other reagents, producing false positive
with appropriate control strains to frequency for checking positive and staining results. Given the widespread
ensure that it is being performed negative reactivity of the BACTEC NAP use of acid-fast stains with the
accurately and all components of the test used to identify M. tuberculosis increasing incidence of mycobacterial
procedure continue to work properly. should be changed from each day of use disease, it is critical that the accuracy of
This routine control procedure must be to each week of use. This commenter these tests be verified each day of use.
performed each day of patient testing or suggested the requirement for testing a Therefore, we are deleting the
can be performed weekly. The weekly positive control each day of use could requirements formerly at §§ 493.1229(b)
QC testing will be deemed to meet CLIA be satisfied by subculturing the growth through 493.1229(c) for testing
requirements, if performed as specified from the BACTEC bottle to a solid fluorochrome and conventional acid-fast
in the approved procedure providing media to detect appropriate colony and stains each week of use. The
equivalent quality testing in Appendix microscopic morphology. requirement for testing conventional
C of the State Operations Manual (CMS Response: The control requirements acid-fast stains will now default to the
Pub. 7). The control organisms must be were written to address test complexity general control requirement for stains
within established control limits before and specialties or subspecialties of formerly at § 493.1218(f)(2) (now at
patient results can be reported. testing, not specific test systems or § 493.1256(e)(2)) that requires testing
Although we did not intend for the procedures. Test-specific CLIA staining materials for intended
requirements at §§ 493.1227(c) and regulations are only developed when reactivity each day of use. For stains
(c)(2) to appear contradictory, we are tests are not adequately addressed in the that provide positive and negative
revising the language now at general or specialty or subspecialty reactivity (intended reactivity), we are
§ 493.1261(b) for clarification of these requirements. The commenter requested revising the language to clarify that
requirements. In addition, we are a change in CLIA regulation because of stains must be tested with positive and
making conforming changes to the the expense of performing controls each negative controls each day of use. By
language pertaining to the requirements time the BACTEC NAP test is set up. eliminating the subspecialty
for antimycobacterial and antifungal The alternative method that the requirement for fluorochrome acid-fast
susceptibility testing for consistency commenter suggests for a positive stains, the general control requirement
and to be current with testing performed control is not actually a control on the for fluorescent stains formerly at
in these subspecialties. These ability of the NAP test to inhibit growth § 493.1218(f)(3) (now at
requirements, formerly at §§ 493.1229(d) of M. tuberculosis, but is a confirmatory § 493.1256(e)(3)) becomes applicable to
and 493.1231(d), are now at test for the presence of this organism. these procedures. This general
§§ 493.1262(b) and 493.1263(b). Although we agree with confirming requirement specifies testing for
Comment: A number of commenters results of the NAP test, it is not the same positive and negative reactivity each
stated the control requirements for as using positive and negative control time of use. It is appropriate to require
identification procedures used in organisms to check the NAP vials for the same control testing for
mycobacteriology at § 493.1229(a) their ability to inhibit growth of M. fluorochrome acid-fast stains as are
should not selectively require positive tuberculosis and to allow growth of required for all other fluorescent stains.
and negative acid-fast control organisms other mycobacteria. However, we Comment: One commenter
to check the iron-uptake test each day understand the financial concerns recommended the deletion in
of use while requiring only a positive associated with running positive and bacteriology of testing positive and
acid-fast control for all other negative controls each day of use for negative organisms each week of use for
procedures. The commenters this test. Since the test has a growth acid-fast stains as required in
recommended that all identification control included as part of each test, § 493.1227(a)(2) and replacement of the
procedures used in mycobacteriology be and the manufacturer indicates the mycology term ‘‘acid-fast stain’’ at
tested each day of use with an acid-fast media is stable and does not § 493.1231(c), with ‘‘modified acid-fast
organism that produces a positive result, recommend testing positive and stain.’’ This commenter emphasized that
and an acid-fast organism that produces negative organisms as frequently as each acid-fast stains are used in
a negative result. day of use, we agree with the mycobacteriology rather than
Response: We agree with these commenter that laboratories should only bacteriology, and that the procedure for
commenters and because the incidence be required to check positive and staining used in mycology is a
of infection caused by a variety of negative control organisms each week of modification of the acid-fast stains
mycobacteria is increasing significantly, use. In addition, we are specifying this performed in mycobacteriology.
Response: We agree with this Comment: A commenter requested Other commenters objected to including
commenter on both of these points. clarification of the control requirements two control materials each time patient
Although acid-fast stains are for virology as they pertain to direct testing is performed. One commenter
occasionally performed in bacteriology, antigen detection. This commenter thought only a positive control was
by deleting the requirement in recommended the addition of a necessary for immunology tests if the
bacteriology for testing acid-fast stains statement to § 493.1235 following patient results were negative.
each week of use, it defaults to the paragraph (c) that would read ‘‘The Response: We agree with the
general requirement formerly at above QC requirements are not commenters who objected to the
§ 493.1218(f)(2) (now at applicable to virology testing performed syphilis serology and routine
§ 493.1256(e)(2)) that requires using direct antigen detection immunology requirements requiring two
laboratories to test staining materials for methods.’’ control materials each time patient
their intended reactivity (including Response: We agree with the testing is performed. With the
positive and negative reactivity, as commenter that the wording formerly at development of more accurate and
appropriate) each day of use. We agree § 493.1235(c) needs clarification. There stable test systems, the requirements
with the commenter that the staining are several types of tests that identify formerly at § 493.1239(b) and
procedure in mycology is a modification viruses, but this requirement only § 493.1241(a) for assaying controls
of acid-fast stain used in applies to cell culture methodologies concurrently with patient specimens are
mycobacteriology; therefore, we are used to isolate and identify viruses. excessive for many of the test systems.
deleting the requirement formerly at Therefore, we are changing the language We are, therefore, deleting these
§ 493.1231(c) for performing control for this requirement, now at requirements. Laboratories performing
testing each week of use for (modified) § 493.1265(a), to make it specific to cell these tests will now need to meet the
acid-fast stains. Again, this results in the culture methodologies. applicable control procedures at
control requirement for these stains § 493.1256. In addition, the laboratory
Sections 493.1237 Condition:
defaulting to the general requirement for must meet the requirements that pertain
Diagnostic Immunology; 493.1239
testing each day of use and is reasonable to establishing or verifying a test
Condition: Syphilis Serology; and
based on the fact that we are now system’s performance specifications
493.1241 Condition: General
requiring positive and negative controls before putting a new test system into
Immunology
for all acid-fast stains each day of use. routine use formerly at § 493.1213 (now
Comment: One commenter stated that Specific comments received and at § 493.1253).
the control regulation for mycology and response to comments regarding We disagree with the comment that
mycobacteriology should require the use §§ 493.1237, 493.1239, and 493.1241 are testing only a positive control is
of a safety cabinet when testing in these set forth below. sufficient if the patient results are
specialty areas. Comment: A commenter stated negative. Laboratories, at a minimum,
Response: We agree with the § 493.1239(e) and § 493.1241(d), which must follow the manufacturer’s
commenter that safety is an important refer to facilities manufacturing blood instructions and for qualitative tests,
factor in laboratory testing, formerly at and blood products, should be deleted. assay a positive and negative control
§ 493.1204(b) (now at § 493.1101(d)) and This individual believes CLIA each day of patient testing (now at
laboratories are required to maintain a regulations should not cover § 493.1256(d)(3)(ii)). For procedures
safe testing environment. Safety manufacturing requirements. producing graded or titered results, a
precautions must be established and Response: We disagree with the control material with graded or titered
observed to ensure protection from commenter. These requirements refer to reactivity, as applicable, and a negative
biohazardous materials. Under testing requirements under CLIA control material must be assayed each
§§ 493.1445(e)(2) and 493.1407(e)(2), the regulations (donor specimens) day testing is performed formerly at
laboratory director is responsible for regardless of where the testing is §§ 493.1239(b) and 493.1241(a) (now at
ensuring a safe environment is provided performed. However, we are moving § 493.1256(d)(3)(iii)). The control
for employees conducting non-waived these requirements, formerly under the material supplied in commercial kits
testing. In addition, other government subspecialties of syphilis serology and (test systems) may be used to meet the
agencies enforce State and local laws general immunology, and placing them requirements formerly at §§ 493.1239(b)
and other Federal standards that ensure with other requirements addressing the and 493.1241(a) (now at
protection of employees and the public immunohematological collection, § 493.1256(d)(3)(iii)) providing the
from biohazardous materials. These processing, dating, labeling, testing, and material is of known reactivity (titered
agencies include the Occupational distribution of blood and blood or graded, as applicable) and is not the
Safety and Health Administration and products now at § 493.1271, same material used to establish a cutoff
the Environmental Protection Agency. Immunohematology (formerly at or calibrate the test system if calibration
Comment: One commenter stated that § 493.1273(a)). of the test system is required (now at
the wording at § 493.1235(c) is Comment: One commenter requested 493.1256(d)(9)).
inappropriate. The commenter clarification of the QC requirements for
recommended the replacement of the serological testing (both syphilis Section 493.1245 Condition: Routine
word ‘‘culture’’ (referring to serology and general immunology) to Chemistry
uninoculated controls) with ‘‘incubate’’ run patient specimens concurrently Specific comments received and
or ‘‘hold.’’ This individual stated that with a positive serum control of known response to comments regarding
the use of the term culture as specified titer or controls of graded reactivity, if § 493.1245 are set forth below.
at § 493.1235(c) generally means to applicable, and a negative control. Comment: One commenter expressed
inoculate and inspect for growth. Specifically, this commenter questioned concern that §§ 493.1245(c) and (d)
Response: We agree with this if these requirements refer to the could be interpreted to mean that the
commenter and are replacing the term additional controls run on a new kit to same material could be used to calibrate
‘‘culture’’ with the term ‘‘incubate’’ verify reproducibility, or if they pertain the instrument and verify or control the
formerly at § 493.1235(c) (now at to the daily testing of the positive test run for blood gas analyzers. The
§ 493.1265). controls supplied in commercial kits. commenter stated that this would not
detect problems arising from include one sample of control material groups reported by the laboratory using
deteriorated or contaminated calibrating each time patient samples are tested. thin layer chromatography on each plate
solutions. The commenter also This final rule provides minimum or card ensures appropriate
recommended the reference to requirements. Based on the laboratory’s identification of the substances or drugs
calibrators be deleted from these verification of the test system’s in patient specimens.
sections and that control testing be performance specifications before
Section 493.1253 Condition:
performed using only control material. routine patient use (now at § 493.1253)
Response: We agree with this Hematology
and establishment of its control
commenter. It was never our intent to procedures (now at § 493.1256(d)), the Specific comments received and
infer by the wording of these laboratory may determine that it needs response to comments regarding
requirements that calibration material to run additional control materials or § 493.1253 are set forth below.
used to calibrate a test system could be run control materials at a more frequent Comment: We received several
used as a control to monitor the test interval to assure accurate and reliable comments requesting the deletion of QC
system’s performance. However, we test results. requirements in hematology because
allow the use of calibration material as they would increase laboratory costs.
a control material provided it is from a Section 493.1249 Condition: Response: We agree with the
different lot number than that used to Toxicology commenters that the requirement to
calibrate the test system or establish a Specific comments received and include two levels of control material
cut-off. Therefore, we are clarifying the response to comments regarding each 8 hours of testing for automated
use of calibration materials as control § 493.1249 are set forth below. hematology analyzers (for example, cell
materials (now at § 493.1256(d)(9)), and Comment: One commenter asked that counters and differential counters) is
eliminating the terms ‘‘calibration’’ and the term ‘‘drug abuse screening using somewhat excessive in light of the
‘‘calibration material’’ from the blood thin layer chromatography’’ at proven stability and reliability of these
gas analysis requirements (now at § 493.1249, Toxicology be modified to instruments. Therefore, we are deleting
§ 493.1267). read ‘‘drugs-of-abuse screening using the specialty-specific control
Comment: One commenter stated thin layer chromatography’’ (‘‘drugs-of- requirement for automated hematology
testing one sample of blood gas control abuse’’ is defined by the National analyzers formerly at § 493.1253(b), and
per 8 hours of patient testing is not Institute for Drugs of Abuse now are requiring laboratories to meet the
sufficient and is inconsistent with the National Substance Abuse and Mental general control requirements (now at
general requirement for quantitative Services Health Administration § 493.1256(d)) when using automated
tests at § 493.1218(b)(2) that requires Laboratory Certification Program). This hematology analyzers. However, the
two controls of different concentrations commenter also requested deletion of manufacturer’s instructions and the
with each run of patient specimens. the requirement under § 493.1249(b) for laboratory’s evaluation of the
This commenter recommended that at at least one control sample to be instruments’ stability, environmental
least two levels of control be required processed and included in each effects, and operator variance will
every 8 hour shift. chamber, stating that all environmental, determine the actual number, type, and
Response: We revised the general chemical and material variables within frequency of testing control materials.
control requirement formerly at a chamber are visualized by running At a minimum, the laboratories will
§ 493.1218(b) (now at § 493.1256(d)). calibration materials. The commenter have to test two control materials of
The requirement now specifies, at a added that controls should be analyzed different concentrations each day.
minimum, assaying two levels of control with each run, and that each run should Comment: One commenter requested
materials each day patient specimens not exceed a 24 hour period. that we remove the requirement for
are tested. We are deleting the term Response: We agree with the duplicative testing of patient and
‘‘run’’ from the regulation. Also, commenter that the control control specimens for manual
laboratories must perform control requirements formerly at § 493.1249 are coagulation tests, as required at
testing using the number and frequency not clear; therefore, we are revising the § 493.1253(d)(2), since proficiency
specified by the manufacturer or language to clarify the requirements. We testing requirements do not allow for
established by the laboratory when are moving the requirements for thin duplicative testing.
those frequencies meet or exceed the layer chromatography to Response: We disagree with the
minimum requirement. Therefore, the § 493.1256(d)(4) under Control commenter and are retaining the
minimum control requirement for procedures. In addition, we are revising requirement for duplicative testing of
quantitative tests, unless a more the term ‘‘drug abuse screening’’ to read patient specimens and control materials
frequent interval is recommended by the ‘‘all known substances or drug groups’’ for manual coagulation testing (now at
test system’s manufacturer or the identified and reported by the § 493.1269(c)(2)). CLIA regulations for
laboratory, is two control materials of laboratory, to accommodate the wider proficiency testing (PT) (§ 493.801(b)(2))
different concentrations each day use of the technology. However, we require the laboratory to test PT samples
patient specimens are tested. disagree with the commenter’s the same number of times that it
The requirement for one control statement that analyzing one control routinely tests patients’ samples.
material per 8 hours for blood gas material per 24 hours is sufficient. If Therefore, since patient specimens must
analyses, formerly at § 493.1245 (now at extractions and tests are performed be routinely tested in duplicate, PT
§ 493.1267) exceeds these general QC more frequently than once per 24 hours, samples for manual coagulation testing
requirements. The blood gas control each ‘‘plate’’ or ‘‘card’’ (formerly must also be tested in duplicate.
requirements also require the laboratory referred to as ‘‘chamber’’) must be
to use a combination of control spotted with at least one sample of Section 493.1257 Condition: Cytology
materials that check low and high control material to ensure that and Section 493.1259 Condition:
values each day of testing. In addition, appropriate separation, and as Histopathology
for blood gas instruments that do not applicable, extraction took place. The Approximately 66 percent of the
internally verify calibration at least inclusion of a calibration material 1,030 comments received concerning
every 30 minutes, the laboratory must containing all known substances or drug the final rule with comment period,
subpart K, were in response to the each person examining slides and that half slide. Second, on January 19, 1993,
cytology requirements. The comments at least every 6 months, the technical we published a final rule with comment
were primarily from professional supervisor must re-evaluate and adjust, period in the Federal Register (57 FR
organizations, cytotechnologists, if necessary, each individual’s workload 5212) removing gynecologic
pathologists, and other physicians. The limit. In addition, we are emphasizing preparations. On July 22, 1993, we
major issues that commenters addressed that the workload limit applies only to published a technical correction notice
include— individuals and does not apply to in the Federal Register (58 FR 39154)
(1) Workload limits; (2) review of automated slide examination systems that inadvertently reinserted
reactive reparative cases by a technical that may be used to screen slides and gynecologic preparations. In addition,
supervisor; (3) the 10 percent rescreen identify those smears requiring no Cytyc, manufacturer of ThinPrep TM,
of negative cases screened by a human microscopic examination. agrees that a 200-slide workload limit is
cytotechnologist; and (4) the 5-year Comment: One organization asked too high for gynecologic preparations
retrospective review of negative smears whether the workload requirements are and has requested that the 200 slide
from patients with a current high grade applicable to technical supervisors or workload limit not be applicable to
lesion. only to cytotechnologists. Several gynecologic slides. We agree with the
Specific comments and response to commenters suggested the workload commenters and Cytyc corporation, and
comments regarding §§ 493.1257 and requirement only applies to we are eliminating gynecologic slides
493.1259 are set forth below. cytotechnologists. from the 200-slide workload limit (now
Comment: Several commenters stated Response: The workload requirements at § 493.1274(d)(2)(iii)). The 200-slide
the language ‘‘non automated apply to any individual who performs workload limit will only apply to
microscopic technique’’ used to primary screening of cytology slides. nongynecologic slides.
describe the slides that are counted in This may be a technical supervisor or a Comment: Many Commenters and the
the workload limit is inappropriate and cytotechnologist. We are also clarifying Cytology organizations agreed that a
might be confused with slides that are that while tissue pathology slides and workload limit was appropriate for
screened using a motorized mechanical previously examined gynecologic and gynecologic preparations. However,
stage or with slides that are read by an nongynecologic slides are not included they were opposed to establishing a
automated instrument. in the 100-slide workload limit for workload limit for nongynecologic
Response: We agree with the technical supervisors, the technical smears because these preparations vary
commenters and are removing the supervisor must subtract the time spent greatly in specimen type or source,
wording ‘‘non automated microscopic evaluating these slides and the time preparatory techniques, and cellularity
technique.’’ We also want to emphasize spent on any nonscreening duties from requiring various time frames for
that slides that are read with a human the time spent screening slides to evaluation. The commenters
component must be included in the 100 appropriately adjust the workload. acknowledged the difficulty in
slide limit; slides that are read by an Comment: Many commenters and the establishing a workload limit for
automated instrument that do not cytology professional organizations individuals who examine
require human review are not included opposed the workload provision to nongynecologic preparations
in the workload limit. count as one-half slide those smears exclusively or a combination of
Comment: A number of commenters made using automated, semiautomated, gynecologic and nongynecologic smears.
and one cytology organization were or other liquid-based slide preparatory For fine needle aspirations, several
opposed to establishing the workload techniques that result in cell dispersion organizations suggested using the
limit at 100 slides examined in a 24 over one-half or less of the slide. Some methodology employed by New York
hour period. A few commenters felt the commenters indicated that this State to prorate nongynecologic
workload limit was too restrictive, while workload limit should apply only to preparations, that is, for cases involving
other commenters and the cytology nongynecologic preparations, while one to three slides, each slide is counted
organization indicated the limit was too others thought it premature to use this as one and for cases having four or more
high. calculation for any cytologic slides, a maximum of three slides are
Response: The CLIA statute at section preparations until sufficient scientific counted for workload purposes.
353(f)(4)(B)(i) specifically states that the studies have been completed to Response: We agree with the
standards must establish ‘‘the maximum document the establishment of a commenters that it is easier to establish
number of cytology slides that any workload limit appropriate for these a workload limit for gynecologic smears
individual may screen in a 24 hour preparatory techniques. than for nongynecologic preparations
period.’’ Limiting the number of slides Response: In order to address because of the variability in
that may be examined in 24 hours to no concerns of the commenters, we are nongynecologic preparations; however,
more than 100 is the absolute maximum making several clarifications. First, the the statute requires us to determine the
workload limit for an individual. 200-slide workload limit was initially maximum number of cytology slides
However, we agree with the commenters established in the February 28, 1992 that an individual can screen in a 24-
that this may not be an appropriate final rule with comment period hour period. Therefore, the workload
workload for all individuals. To clarify published in the Federal Register (57 limit is applicable to all cytology slides,
our position, formerly at FR 7002) in response to innovations in including gynecologic and
§ 493.1257(b)(1) (now at cytology preparatory techniques and nongynecologic preparations.
§ 493.1274(d)(2)), we specify that the acknowledgment that slide preparations Concerning the New York State
Federal workload limit was not to be that only occupy a portion of the slide proration of nongynecologic slides, this
used as a performance target for will not count as a whole slide. Slide practice is no longer in use in New
cytology personnel. In addition, we preparations (gynecologic and York.
specified formerly at § 493.1257(c)(4) nongynecologic) made using automated, Comment: Several individuals asked
(now at § 493.1274(d)(1)) that the semi-automated, or other liquid-based for clarification on the specific
cytology technical supervisor must preparatory techniques that result in a guidelines that a technical supervisor
establish a workload limit (not to exceed specimen that only occupies a small should use to determine the maximum
100 slides examined per 24 hours) for portion of the slide, are counted as one- workload for an individual. Some
commenters noted the technical having ‘‘reactive and reparative’’ percent rescreen before reporting patient
supervisor may have to justify a changes that would have exhibited results.
workload that is lower than 100 slides marked or extensive cellular changes on Response: The CLIA statute requires
to hospital and laboratory technical review will, therefore, be ‘‘* * * random rescreening of cytology
administrators. classified as ASC–US or as having a specimens determined to be in the
Response: Formerly at squamous cell abnormality under the benign category * * *’’ Accordingly,
§ 493.1257(c)(4)(i), individual workload Bethesda terminology. As specified at random rescreening of negative cases is
is based on the performance evaluation § 493.1274(e), all of these slides are required in CLIA rules. We view the 10
described formerly at § 493.1257(c)(3). required to be reviewed by the technical percent rescreen as a minimum
Therefore, we are revising the supervisor. However, we have retained requirement and only one component of
requirement, now at § 493.1274(d)(1)(i), the classification reactive and the laboratory’s control procedures and
to make it more understandable. ‘‘reparative changes,’’ and similar QA activities. In addition, rescreening is
Performance must be evaluated using cellular changes under the Bethesda supported by the results of cytology
the following: (1) Re-evaluation of 10 category ‘‘Negative for Intraepithelial surveys conducted under CMS contract
percent of the cases interpreted to be Lesion or Malignancy’’ that would that includes rescreening approximately
negative by cytotechnologists; and (2) formerly have been categorized as 0.1 percent of the laboratory’s caseload.
comparing the cytotechnologist’s reactive or reparative to encompass In many of these surveys, diagnostic
interpretation with the final diagnosis those slides needing review by the discrepancies were noted between the
on cases of atypical squamous cells of technical supervisor. Technical contractor’s evaluation of patient
undetermined significance (ASC–US), supervisors continue to have the specimens and the results reported by
low-grade squamous intraepithelial discretion to review more cases as the laboratory, even though the sample
lesion(LSIL), high-grade squamous necessary to train and manage rescreened was less than 10 percent of
intraepithelial lesion (HSIL), glandular cytotechnologists under their the laboratory’s caseload. The control
epithelial cell abnormalities, or other supervision. Although we are not procedures, including the 10 percent
malignant neoplasms. However, the requiring the use of the Bethesda rescreen, assess the quality of the
evaluations listed in the former CLIA terminology, the majority of the laboratory’s results, and the rescreen
regulations must be viewed as minimal laboratories have adopted it, and we must be completed before issuing
requirements and the laboratory may encourage other to do the same. patient reports on the slides selected for
have additional mechanisms or criteria Comment: One organization stated the 10 percent rescreen as specified
to evaluate individual performance. For that the technical supervisor’s signature formerly at § 493.1257(d)(1)(iii) (now at
example, the following provisions in the on the worksheet is acceptable § 493.1274(c)(1)(ii)).
CLIA regulations may be used: (1) documentation for the review of
Comment: One commenter asked
Number of discrepant findings on the abnormal gynecologic cases. For
whether the 10 percent re-evaluation of
retrospective review of previous nongynecologic cases, the organization
negative cases could be performed by
negative cases from patients with a suggested that laboratories allow the
current HSIL, adenocarcinoma or other technical personnel to verify the final the same individual who performed the
malignant neoplasm; (2) individual computer generated report that would primary review.
statistics evaluated against the include the name of the technical Response: The 10 percent rescreen of
laboratory’s overall statistics; and (3) supervisor who reviewed the case. negative cases is one provision of the
competency assessment activities. Another commenter asked for cytology control procedures specified
Comment: Many of the commenters clarification on electronic signatures formerly at § 493.1257(d) requiring
and the cytology organizations and whether CLIA regulations allow laboratories to have a program designed
suggested that the requirement for electronic requisitions. to detect errors in cytology
confirmation of cases by the technical Response: We do not believe that any examinations. This provision is now at
supervisor be limited to those having change in the CLIA regulations is § 493.1274(c). Ten percent of the cases
atypical squamous or glandular cells, or appropriate. The final report must be interpreted as negative by
any premaligment or malignant cell verified by the technical supervisor who cytotechnologists must be reevaluated
changes. The commenters suggested reviewed the case and signs the report, by a cytology technical supervisor
deleting the reference requiring and electronic signatures must be qualified under §§ 493.1449(b) or
confirmation of ‘‘reactive or reparative authorized and verified by the technical 493.1449(k), a cytology general
changes,’’ stating that the requirement supervisor who signs the report. As supervisor qualified under
was excessive. Other commenters specified at § 493.1241, electronic § 493.1469(b)(2), or a cytotechnologist
recommended changes to allow requisitions are acceptable, as long as qualified under § 493.1483 who has the
technical supervisors the discretion to the requisition contains the required experience specified in § 493.1469(b)(2).
determine the level of supervisions, that information. For laboratories with a solo pathologist
is, review of cases with benign cellular Comment: Several commenters, (no cytotechnologists), the 10 percent
changes, needed by each employee. In including one cytology organization, rescreen need not be performed;
addition, several commenters suggested disagreed with requiring laboratories to however, the following cytology QC
we revise the language to include the rescreen 10 percent of the cases procedures must be performed: a
Bethesda terminology. interpreted to be normal or negative by laboratory comparison of clinical
Response: We have not removed all cytotechnologists. One organization information and histopathology reports
reference to reactive and reparative stated the 10 percent rescreen is a (as specified at § 493.1274(c)(2)), a
changes because many laboratories still statistically invalid mechanism for retrospective rescreen of normal and
use this classification. The regulation, reducing the false negative rate and negative cases received within the
however, incorporates the Bethesda suggested the requirement be replaced previous 5 years from a patient with a
terminology, which provides for a by a goal-oriented statistically valid current high grade lesion (as specified at
uniform categorization of the cellular system for promoting laboratory QC. § 493.1274(c)(3)) and annual statistical
changes seen in gynecologic cytology. One organization was opposed to evaluation (as specified at
Most of the slides formerly classified as requiring laboratories to complete the 10 § 493.1274(c)(5)).
Comment: Many cytology Response: We established these making the change to § 493.1273 rather
organizations disagreed with requiring requirements as a result of comments than the personnel requirements in
review of all normal or negative slides provided in response to the proposed subpart M, because in this final rule, we
from the previous 5 years for any patient rule that was published on May 21, are limiting the personnel revisions to
having a current high grade 1990 in the Federal Register (55 FR the phase-in provisions addressed in the
intraepithelial lesion or above. The 20896). The commenters stated that December 28, 2001 proposed rule. HHS
commenters felt that the 5-year review reviewing the laboratory’s data provided received numerous personnel comments
was unreasonable and unnecessarily useful information on overall laboratory in response to the February 28, 1992
burdensome and suggested that the practice as well as individual final rule with comment period which
review include only the two most recent performance. We believe these we intend to address in a future
smears, if available in the laboratory. A requirements have provided valuable regulation.
number of commenters noted the error information for assessment of laboratory
Section 493.1265 Condition:
at § 493.1257(d)(3) in referring to and individual performance; therefore,
Histocompatibility
patients with ‘‘a current high grade or we are not making any revisions.
above intraepithelial lesion . . .’’ and However, laboratories may document Specific comments received and
suggested rewording the requirement for situations that affect the laboratory’s response to comments regarding
retrospective review of negative cases statistics and individual case reviews. § 493.1265 are set forth below.
from patients having a ‘‘current high Comment: One cytology organization Comment: Several commenters were
grade intraepithelial lesion or cancer.’’ was opposed to requiring laboratories to pleased with the final CLIA rule for
Response: We are not reducing the document cases for which histologic histocompatibility testing and felt the
requirement for review of negative cases reports were unavailable for comparison majority of the concerns raised over the
from the previous 5 years for patients with abnormal gynecologic results, proposed rule had been addressed. They
having a current high grade stating that it was time consuming and noted the requirements now generally
intraepithelial lesion or cancer because burdensome and provided no benefit to reflect the state of the art laboratory
the law requires ‘‘. . . for each the patient. practices in this specialty area of testing
abnormal cytological result, rescreening Response: In an attempt to minimize that is continuing to evolve.
of all (emphasis added) prior cytological the burden, (now at Response: We appreciate this
specimens for the patient, if available.’’ § 493.1274(c)(5)(iv)), we are requiring acknowledgment of the efforts made in
However, we appreciate and agree with documentation of only the number of developing the histocompability QC
the commenters’ suggestion about cases that have histology correlation. requirements specified in the final rule
rewording the requirement, formerly at We believe this information is necessary with comment period that was
§ 493.1257(d)(3) (now at to determine the laboratory’s success in published on February 28, 1992 in the
§ 493.1274(c)(3)) to reflect current obtaining histology reports for the Federal Register (57 FR 7170). In our
terminology. histology and cytology correlation. continuing endeavor to represent
Comment: One organization asked for current technology and practice, we are
Section 493.1259 Condition: updating some of the terminology and
clarification on the time frame for
Histopathology references used in this section. We are
completion of the retrospective review
of cases with a current high grade lesion Specific comments received and also deleting several requirements that
or above and the histology and cytology response to comments regarding are duplicative of requirements found
correlation. § 493.1259 are set forth below. elsewhere in the CLIA regulation. In
Response: The retrospective review Comment: Two medical professional addition, we are adding clarifying
and the histology and cytology organizations disagreed with the language and reorganizing the
correlation are part of the control requirements at § 493.1259(c) that requirements in this section that apply
procedures and must be completed in a precluded neurologists from examining to HLA typing, disease associated
timely manner. Since there is a nerve and muscle biopsies. Also, in May studies, antibody screening,
possibility that this QC activity could 1993, CLIAC recommended that crossmatching, transplantation, and
result in the issuance of a corrected neurologists with specialized training general requirements that apply to every
report that may affect patient treatment, and board certification qualify as histocompatibility laboratory regardless
the laboratory must have procedures in technical supervisors, general of the testing and services offered by the
place that include time frames for these supervisors, and testing personnel of laboratory.
activities. neuromuscular histology. Without Comment: One commenter requested
Comment: Several commenters and recognition of this training, neurologists the requirements for histocompatibility
cytology organizations disagreed with would be required to refer testing be separated into three groups:
requiring laboratories to compare the neuromuscular tissue specimens to an solid organ transplantation, including
case reviews of each individual with the anatomic pathologists for examination. renal; bone marrow transplantation; and
laboratory’s overall statistical values. Response: We are amending the histocompatibility testing for
The commenters stated that the case histopathology QC requirements transfusion services.
mix (specimens from various clinics formerly at § 493.1259(c) (now at Response: We acknowledge that the
with different patient populations) § 493.1273(c)) to allow individuals who organization of the histocompatibility
varies and these statistics should not be have successfully completed a training requirements found in the final rule
used to assess individual performance. program approved by HHS to examine with comment period may have caused
In smaller laboratories the statistical and provide reports for neuromuscular some confusion to the reader trying to
comparison may not be valid due to the pathology. In Appendix C of the State determine what testing requirements
small numbers. It was suggested that Operations Manual (CMS Pub. 7), apply to each type of organ or tissue
laboratories be given flexibility to subpart K, we will specify that the transplant. While there are various ways
determine the best approach for training program developed by the to group the requirements in this
implementing the control procedure American Academy of Neurology specialty, we are reorganizing this
requirements and evaluating individual Committee for Neuromuscular section by first delineating the general
performance. Pathology is approved by HHS. We are requirements for histocompatibility
testing (now at § 493.1278(a)) and lymphocytotoxicity technique used in acknowledged that the cost of monthly
specifying the requirements for HLA the final donor crossmatch. screening can be prohibitive and
typing (now at § 493.1278(b)), disease Response: Histocompatibility testing suggested there may be some instances
associated studies (now at is a rapidly evolving, highly complex when monthly screening may not be
§ 493.1278(c)), antibody screening (now specialty. Its role in predicting long- necessary. However, most commenters
at § 493.1278(d)), crossmatching (now at term allograft survival is the subject of agreed that studies need to be done to
§ 493.1278(e)) and transplantation (now numerous research studies. Not all determine the optimum frequency of
at § 493.1278(f)). In addition, we believe antibody reactions have a defined antibody screening.
this reorganization, along with other specificity, and the clinical relevancy of Response: We agree with the
revisions, will greatly enhance the each antibody has not been established. commenters and recognize the
readability of this section and clarify the Mandatory antibody identification may importance of developing an accurate
requirements that must be met for each be impractical, if not impossible, and immunological history of the potential
type and level of histocompatibility uninformative in these cases. However, transplant recipient and the difficulty of
testing performed by the laboratory. we agree that antibody identification identifying and obtaining information
Comment: One commenter pointed must be performed when appropriate to on all potential sensitizing events. We
out the requirement at § 493.1265(a)(4) support clinical transplant protocols also appreciate the efforts to control
that addresses reagent typing sera and § 493.1445(e)(3)(i) requires the healthcare costs by eliminating
inventories prepared in-house should laboratory director to select test unnecessary and or redundant testing.
also require that the specificity of the methods that are capable of providing To provide flexibility and allow
reagent be indicated. The commenter the quality of results required for patient responsiveness to emerging research
also requested clarification of the term care. It is the laboratory director’s data and information, we are revising
‘‘typing tray’’ used at § 493.1265(a)(9)(i) responsibility to institute more stringent the requirements formerly at
since the term can refer to any 96, 72, testing protocols as necessary for quality §§ 493.1265(a)(2)(ii) and (a)(8)(i) (now at
or 60 well microtiter tray used in the patient care. Therefore, we are adding a §§ 493.1278(d)(4) and (d)(5)) to require
HLA laboratory. The commenter stated requirement at § 493.1278(d)(7) for the laboratory to make a reasonable
that without clarification, it is unclear laboratories that perform antibody attempt to have available monthly
whether the control requirements identification to have available and serum specimens for all potential
specified at this requirement refer only follow written criteria and procedures transplant recipients for periodic
to trays used for HLA typing or if they for antibody identification to the level antibody screening and crossmatch. In
include trays run in an attempt to appropriate to support clinical this regard, the laboratory must have
identify the presence of circulating HLA transplant protocol. available and follow a policy, consistent
We agree with the commenter that the with clinical transplant protocols for the
antibodies.
laboratory must use a technique that frequency of screening potential
Response: We agree that reagent detects HLA-specific antibody with a transplant recipient sera for preformed
specificity must be indicated on the specificity equivalent or superior to that HLA-specific antibodies.
laboratory’s in-house prepared reagent of the basic complement-dependent Comment: Three commenters noted
typing sera inventory and are amending microlymphocytotoxicity assay. In that DNA typing involves the genes
the requirement now at § 493.1278(a)(3) addition, to detect antibodies to HLA rather than the expressed antigens;
accordingly. Class II antigens, the laboratory must therefore, § 493.1265(a)(10) would be
The commenter is correct to question use a method that distinguishes more accurate if changed to read,
the scope of the requirement formerly at antibodies to HLA Class II antigens from ‘‘Compatibility testing for HLA class II
§ 493.1265(a)(9)(i) that addressed antibodies to Class I antigens. We are polymorphisms should utilize
control requirements for typing trays. In adding these two new requirements at techniques, for example, mixed
addition, the term ‘‘typing tray’’ is §§ 493.1278(d)(1) and 493.1278(d)(2). lymphocyte culture, homozygous typing
somewhat restrictive in that testing To ensure quality laboratory practices cells, or DNA analysis.’’
performed with newer and emerging and for consistency with the two new Response: We agree with the
technologies may not necessarily use requirements, we are specifying that commenters that the wording of the
microtiter trays. Therefore, we are techniques used for crossmatching must requirement formerly at
revising the requirement for be documented to have increased § 493.1265(a)(10) is somewhat
clarification, and, with the sensitivity in comparison with the basic inaccurate and also believe that the
reorganization of this section, complement-dependent requirement may be too restrictive for
§ 493.1278(b)(6) now describes the microlymphocytotoxicity assay (now at future methodologies, technologies, and
controls a laboratory must use for each § 493.1278(e)(1)). In addition, when transplantation protocols. Therefore, we
HLA typing, and § 493.1278(d)(6) performing HLA typing, the laboratory are deleting this requirement for the
addresses the controls a laboratory must must use a technique that is established laboratory to use specific techniques, for
use when performing antibody to optimally define, as applicable, HLA example, mixed lymphocyte cultures, to
screening. Class I and II specificities (now at determine HLA Class II
Comment: One commenter requested § 493.1278(b)(1)). incompatibilities.
that the CLIA regulations mandate HLA Comment: A number of commenters Comment: One commenter stated that
antibody identification when panel were opposed to the elimination of the requirement at § 493.1265(a)(13) to
screening studies indicate the presence mandatory monthly screening for HLA have histocompatibility testing
of a lymphocyte-reactive antibody. In antibodies, since most, if not all, personnel evaluate unknowns on a
addition, the laboratory should laboratories lack access to accurate monthly basis is excessive and should
determine if this is an autoantibody or information regarding each potential be reduced to once every 6 months.
alloantibody. The commenter also transplant recipient’s exposure to Response: Histocompatibility testing
requested the CLIA rule require that the sensitizing events. This is compounded is a highly complex specialty with great
specific technique used in HLA by the probability that not all potential for harm to the patient if the
antibody screening be at least as potentially sensitizing events have been testing is incorrectly performed. CLIA
sensitive as the complement-dependent identified. A few commenters regulations specify formerly at
§ 493.1445(e)(13) that the director has to addition, we believe this less Response: The task of delineating all
ensure that policies and procedures are prescriptive, but laboratory-specific applicable requirements of subpart K for
established for monitoring employee requirement provides the flexibility each specialty or subspecialty of testing
competency and to identify needs for required to ensure laboratory practice would require continuous revision and
remedial training or continuing that is responsive to advances in updating for new test systems and
education. Monitoring employee transplantation medicine and laboratory emerging technologies. For this reason,
competency may include the evaluation methodologies and technology. the requirement (now at § 493.1225)
of previously tested specimens as Comment: One commenter stated that remains unchanged and continues to
unknowns. However, we are deleting the requirement, at § 493.1265(b)(3), to direct laboratories to comply with the
this former requirement at provide the results of the final requirements of subpart K that are
§ 493.1265(a)(13) because we believe it crossmatch before nonrenal solid organ applicable to the testing being
is somewhat duplicative of the transplantation when the recipient has performed. However, Appendix C of the
laboratory director responsibility. demonstrated presensitization is not State Operations Manual will give
Comment: Three commenters, necessarily relevant or realistic for all guidance to surveyors concerning the
including a professional organization, types of grafts. The commenter cited the control requirements for clinical
recommended that living transplants be short viability time of certain organs cytogenetics. As specified now at
deleted from § 493.1265(b)(2) that (heart and lung) and unpublished data § 493.1256(e)(2), each day of use, the
requires the performance of mixed pertaining to the nonrelationship laboratory is required to test the positive
lymphocyte cultures or other augmented between high-titered positive donor T and negative reactivity of staining
testing to evaluate HLA class II cell crossmatches and liver allograft materials to ensure predictable staining
compatibility. The commenters stated survival. characteristics. Media must be checked
that although appropriate for bone Response: We agree with the for sterility and to ensure that it
marrow transplantation, mixed commenter that the period of time that supports growth of the appropriate
lymphocyte culture is performed rarely organs, for example, the liver, pancreas, tissues as required now at
in living-related kidney transplantation and heart remain viable after removal § 493.1256(e)(4). As for materials to
where HLA Class II compatibility and from the donor is often not sufficient for demonstrate chromosome abnormalities,
genetic linkages can be adequately the laboratory to complete the for example, linkage, breakage, or
determined using serological methods. crossmatch. The regulation formerly at translocation, Appendix C of the State
In addition, the commenters maintained § 493.1265(b)(3) (now at Operations Manual (CMS Pub. 7) states
that mixed lymphocyte culture tests § 493.1278(f)(3)) has been revised to that these materials are not routinely
were unnecessary in solid organ require laboratories to develop and available; however, an alternative
transplants and not considered a follow policies for testing and providing procedure for the immediate assessment
contraindication to this type of results of final crossmatches when the and monitoring of all testing over time
transplantation. recipient has demonstrated must be instituted by the laboratory as
Response: We agree with the presensitization by prior serum specified now at § 493.1256(h).
commenters. The phrase, ‘‘and living screening. In addition, the policy must Comment: A few commenters stated
transplants,’’ formerly at address emergency transplant situations laboratory testing of sex chromatin by
§ 493.1265(b)(2), was deleted in a that would not allow time for the Barr body analysis or by ‘‘Y’’ body
technical correction notice published on laboratory to perform prospective analysis is not considered the standard
January 19, 1993. In addition, we crossmatches. In addition, we would of practice for the diagnosis of
recognize the evolving nature of like to clarify that the intent of individuals with sex chromosome
transplant medicine makes it difficult to § 493.1278(f)(3) is not to preclude the aneuploidy, citing the well documented
prescribe standards for testing protocols use of crossmatch-positive nonrenal frequency of mosaicism in individuals
that may be quickly outdated with organs and tissues but to ensure, with sex chromosome aneuploidy that
emerging research data and information, whenever possible, the availability of all leads to false negatives. Therefore, they
for example, graft survival, acute, and pertinent test results on which the strongly recommend not employing this
chronic rejection. For this reason we are physician(s) may base their decision to testing as a screening test and deleting
revising the requirements formerly at proceed with the transplant. it from the list of tests that are
§§ 493.1265(b) and (c) that specified the performed in cytogenetics laboratories.
type of testing to be performed for each Section 493.1267 Condition: Clinical Response: We agree with the
transplant type. We are requiring (now Cytogenetics commenters and are deleting the
at § 493.1278(f)(1)) that laboratories Specific comments received and requirements pertaining to the
performing histocompatibility testing response to comments regarding performance of X and Y chromatin
for transfusion and transplantation § 493.1267 are set forth below. counts for sex determination that were
purposes have available, and follow, Comment: One commenter suggested formerly at § 493.1267(a). In this final
written policies and protocols the cross-references to subpart K at rule at § 493.1276(c), we are now
specifying the histocompatibility testing § 493.1267 list only those portions that requiring full chromosome analysis for
to be performed for each type of cell, apply to cytogenetic testing so that, for sex determination.
tissue, or organ to be transfused or example, the general requirement for Comment: A few commenters
transplanted. The laboratory’s policies testing positive and negative controls is questioned the requirement that
must address, as applicable, testing not referenced. The commenter chromosome resolution be sufficient to
protocols for cadaver donor, living, suggested at the very least, Appendix C support the reported result. One
living-related and combined organ and (Survey Procedures and Interpretative commenter stated that this is a ‘‘catch
tissue transplants; the level of testing Guidelines for Laboratories and 22’’ in that a low resolution study
required to support clinical transplant Laboratory Services) of the State reported as normal in a patient with an
protocols (for example, HLA typing at Operations Manual (CMS Pub. 7) should abnormality only detectable at a higher
the antigen or allele level); and any instruct CLIA surveyors to ignore this level of resolution would be wrong,
additional testing required for patients requirement when inspecting a however, the low resolution analysis
at high risk for allograft rejection. In cytogenetics laboratory. would be in support of the reported
normal diagnosis. The commenters Comment: One commenter a self-funded program, the commenter
suggested establishing a specific band recommended gestational alpha- wondered if the FDA reimbursed the
level of resolution that would be fetoprotein (AFP) be recognized as an CLIA program for these services.
dependent upon the type of study analyte. Gestational AFP testing should Response: The commenter is correct
requested. not be included under Immunology, in questioning the role of the CLIA
Response: We are revising the where AFP is used as a tumor marker. surveyors’ inspection responsibilities.
requirement formerly at § 493.1267(b) Response: Although the analyte We have corrected the citations from 21
(now § 493.1276(b)(2)) for clarity. The alpha-fetoprotein may be used for CFR to specify in 42 CFR part 493 the
requirement now states that the genetic screening, the test does not exact requirements that must be met
resolution used must be appropriate for entail chromosomal examination (that under the CLIA regulations. The revised
the type of tissue or specimen, and that is, cytogenetics). Measurement of this citations are now at §§ 493.1105(a)(1)(i),
the type of study required is based on analyte may be used for non-cytogenetic 493.1271(a)(1) and (b). When reviewed,
the clinical information provided to the purposes. CLIA certifies laboratories in the actual time expended surveying
laboratory. both the subspecialty of routine sections of the FDA’s regulation was
Comment: One commenter suggested chemistry and general immunology for minimal. Sister agencies such as the
that substituting the words gestational and maternal AFP. FDA and CMS frequently assist one
‘‘photographic karyotypes’’ for another without charge when
Section 493.1273 Standard:
‘‘photographs’’ would correctly reflect expenditures to provide such assistance
Immunohematological Collection,
what cytogeneticists read. are de minimis.
Processing, Dating Periods, Labeling and
Response: We are adding new Distribution of Blood and Blood Subpart M—Personnel for Moderate
language to the CLIA regulation Products Complexity (Including the Subcategory)
formerly at § 493.1267(c) (now at Specific comments received and and High Complexity
§ 493.1276(a)) to specify karyotypes in response to comments regarding In the February 28, 1992 final rule
addition to photographs. § 493.1273 are set forth below. with comment period, the personnel
Comment: A few commenters Comment: One commenter requested requirements are located in subpart M
disagreed with the CLIA regulation the addition of requirements to and include qualification requirements
requiring ‘‘appropriate nomenclature’’ § 493.1273 regarding the use of bar code for individuals to direct a laboratory
and felt the CLIA regulation should systems for the identification of blood performing high complexity testing. A
require the use of the International and blood products, stating that phase-in period was provided for
System of Cytogenetic Nomenclature in laboratories should document the individuals with a doctoral degree to
reporting all cases because it is the only accuracy of bar codes before putting the obtain board certification. In response to
recognized system that exists and systems into use, and as a continuing the publication of the date extension
anything else would be homemade and part of quality assurance while the rules, we received comments suggesting
impossible to interpret other than by systems are in use. that we develop alternative provisions
that particular laboratory. Response: We agree with the to qualify individuals with a doctoral
Response: We agree with the commenter that the accuracy and degree on the basis of laboratory
commenters and are replacing the words ongoing reliability of bar code systems training or experience, instead of
‘‘appropriate nomenclature’’ formerly at used for the identification of blood and requiring board certification. On
§ 493.1267(d) (now at § 493.1276(d)) blood products is an important quality December 28, 2001, we published a
with the words ‘‘the International issue for laboratories that use them. proposed rule in the Federal Register
System of Cytogenetic Nomenclature.’’ Laboratories involved in collecting, (66 FR 67163) that included provisions
Comment: One commenter stated that processing, dating, labeling, testing, and to end the phase-in period and revise
failure rate is an aspect of cytogenetic distributing blood and blood products and expand the qualifications required
testing and that it is not addressed by are required to conform to the FDA for an individual with a doctoral degree
CLIA regulations. The commenter also requirements for blood and blood to direct a laboratory performing high
stated that failure rate can provide products at 21 CFR parts 606, 640, 21 complexity testing.
valuable information about a CFR 610.40, and 610.53. Specifically, 21 Following publication of the proposed
laboratory’s capabilities and be easily CFR 606.121: Container label, permits rule, we received 113 comment letters,
evaluated by an individual lacking the use of container labels that bear which contained approximately 300
specific expertise in cytogenetics. The encoded information in the form of comments. Of these, 168 comments
commenter stated that accepted machine-readable symbols approved for agreed with one or more provisions in
standards for study failure rates exist for use by the Director, Center for Biologics the proposed rule, 120 comments
the various types of tests done in Evaluation and Research, FDA, and disagreed with at least one of the
cytogenetic laboratories. refers to FDA’s ‘‘Guideline for Uniform provisions, 6 comments addressed the
Response: We agree that study and Labeling of Blood and Blood education requirements, and 1 comment
culture failure rates can be a useful tool Components,’’ that addresses blood reflected misinterpretation of the
in evaluating a cytogenetic laboratory’s product labeling requirements, proposed requirements. Fifty-three of
performance. However, the study must including standards for bar codes. Also, the 113 comment letters specifically
be evaluated carefully because many 21 CFR 606.140 requires the laboratory addressed qualification requirements for
factors outside of the laboratory’s to have control procedures that provide directors of laboratories performing
control may influence the rates, for for monitoring the reliability, accuracy, histocompatibility testing.
example, specimen transit time and precision, and performance of Specific comments received and
conditions. In addition, what constitutes laboratory test procedures and responses to comments regarding the
failure must be clearly defined. For this instruments. proposed rule are set forth below.
reason, we are not mandating failure Comment: A laboratory surveyor Comment: The majority of the
rates but encourage laboratories to asked why CLIA personnel are comments on the first provision (at the
monitor these rates as part of a QA responsible for surveying large sections proposed and former § 493.1443(b)(3)(i))
program. of the FDA’s regulations. Since CLIA is agreed with requiring board certification
as a qualification requirement for require board recertification when certification to CMS. This information
individuals having a doctoral degree to required by an HHS-approved board. In will be evaluated to determine if the
serve as high complexity laboratory addition, a few commenters disagreed board’s certification requirements are
directors. These commenters with board recertification. comparable to those currently approved
emphasized the role of board Response: A total of eight certification boards.
certification in ensuring that individuals boards have been approved by HHS. With respect to requiring
have specific training and experience, as Four boards are listed in the former recertification, it was always the intent
well as uniform and broad-based regulations at § 493.1443(b)(3)(i): The of the former regulations, that
clinical knowledge, skills and American Board of Medical individuals with a doctoral degree
competencies. In addition, at the CLIAC Microbiology; the American Board of qualifying under § 493.1443(b)(3)(i)
meeting held on January 30, 2002 Clinical Chemistry; the American Board must be, and continue to be, certified by
through January 31, 2002, CLIAC of Bioanalysis; and the American Board an HHS-approved board. If a board
expressed strong support for board of Medical Immunology. On July 8, requires recertification and an
certification for laboratory directors and 1996, we published a notice in the individual fails to recertify and loses
suggested the recent efforts of the boards Federal Register (61 FR 35736), that board certification, this individual
to provide more flexible routes to announced HHS approval of two boards: would no longer meet the director
certification would allow more The American Board of qualification requirement at
individuals to meet the certification Histocompatibility and Immunogenetics § 493.1443(b)(3)(i). In this final rule, and
requirements. CLIAC and other and the American Board of Medical as proposed in the December 28, 2001
commenters also felt that the Genetics. In this final rule, we are proposed rule, we are revising the
documentation of continuing education announcing HHS-approval of two language at § 493.1443(b)(3)(i) for
required for retaining board certification additional boards: the National Registry clarification.
is essential in ensuring that individuals for Clinical Chemistry at the doctoral Comment: A number of comments
maintain the professional abilities level and the American Board of agreed with the second provision (at
needed to direct laboratories that Forensic Toxicology. However, in this proposed § 493.1443(b)(3)(ii)) allowing
provide services in the multifaceted, final rule, we are deleting the reference individuals having a doctoral degree,
constantly changing high complexity at § 493.1443(b)(3)(i) to the specific who are serving or have served as
testing category. The few comments boards approved by HHS. Currently, all directors of laboratories performing high
opposed to board certification indicated HHS-approved boards are listed on the complexity testing under the current
certification does not ensure the Internet at http://www.cms.hhs.gov/clia/ regulations’ phase-in provision, to
performance of individuals and that dirc/con.asp. In the future, boards continue to qualify without obtaining
employee skill validation is the approved by HHS will also be listed in board certification. However, a few
responsibility of the employer. These Appendix C of the State Operations commenters felt this provision should
commenters also noted the absence of Manual (CMS Pub. 7), subpart M. be temporary, with a date specified by
evidence documenting that certified Removing the list of approved boards which board certification would be
individuals perform better than from the regulations and placing the list required to maintain qualification. One
noncertified individuals. in Appendix C will allow greater commenter urged that a date be
Response: We agree with the flexibility to update the list of HHS- established (and not extended) to
comments supporting board approved boards. conclude this qualification provision. A
certification and are maintaining the In response to the comments State Health Department interpreted the
former requirements at suggesting that the criteria for requirements in this provision to mean
§ 493.1443(b)(3)(i) requiring board determining HHS-approval of that a total of 4 years of experience is
certification as one of the pathways for certification boards be included in the required, and that the training and
qualifying individuals with a doctoral regulations, we do not believe that experience and director and/or
degree as directors of laboratories regulations, which specify standards supervisory experience cannot be
performing high complexity testing. that must be met by covered entities, gained concurrently. This commenter
Although certification does not provide should include details of an also suggested this experience be
absolute assurance that individuals will administrative process. All boards postdoctoral experience.
effectively fulfill the responsibilities approved by HHS have been determined Response: We agree the second
required of directors, it is a recognized to have comparable certification proposed qualification provision is
benchmark of competency and an requirements. In the ‘‘Conditions for needed to allow (‘‘grandfather’’)
appropriate mechanism for qualifying Coverage of Services of Independent individuals who have served or are
individuals to serve as laboratory Laboratories’’ published in the currently serving as directors of high
directors. In addition, the ongoing September 19, 1974 Federal Register (39 complexity testing to continue to serve.
continuing education required by each FR 33693), the laboratory director We also agree that a date needs to be
of the HHS-approved boards to retain qualification requirements included specified to conclude this qualification
certification helps ensure these provisions for qualifying individuals pathway and the training and
individuals maintain a current with a doctoral degree. One option was experience requirements clarified;
knowledge base. certification by one of three boards however, we do not agree that the
Comment: A State Health Department (American Board of Medical training and experience must be
and one laboratory professional Microbiology, the American Board of postdoctoral. We believe laboratory
organization requested that all HHS- Clinical Chemistry, and the American training and experience obtained while
approved boards and the criteria for Board of Bioanalysis). Subsequently, all an individual is working toward
board approval be listed in the boards approved by HHS have been obtaining a doctoral degree is pertinent
regulations. One of these commenters determined to have certification and appropriate, and should be
asked whether the phrase ‘‘* * * be requirements comparable to those three considered as meeting the requirement.
certified and continue to be certified boards originally recognized. Any board In this final rule, at
* * *’’ included in the proposed rule at may request HHS approval by § 493.1443(b)(3)(ii), we are specifying
§ 493.1443(b)(3)(i) means that HHS will submitting their request for board February 24, 2003, as the effective date
for this final rule’s personnel increase in the quantity of individuals performing high complexity testing.
qualification requirements, and we are qualified to direct high complexity They suggested that individuals with an
clarifying the training and experience testing at the expense of quality, which appropriate master’s degree and
requirements individuals must meet. To is in part attributed to a competent progressive experience in the clinical
ensure a smooth transition to the new workforce. Although a few commenters laboratory (5 to 10 years) should be able
provisions for directors of high agreed with this proposed provision to to qualify.
complexity testing who are not board provide qualification specifications Response: We believe the doctoral
certified (but who have doctoral based on training and experience in lieu degree is an appropriate minimum
degrees), we will not be holding of board certification, they suggested education requirement for directors of
facilities out of compliance with the revisions to make the provision more laboratories performing high complexity
provisions of the rule concerning stringent and felt continuing education testing. It is commensurate with the
directors who are not board certified should be added to ensure that responsibilities of a high complexity
until the effective date of this new rule, individuals maintain competency. laboratory director, as specified in the
to the extent the facilities are otherwise Response: We agree with the former regulations at § 493.1445, and
in compliance with the requirements for comments expressing disagreement with consistent with the education
laboratory directors. Individuals must, the third proposed qualification requirements and responsibilities
therefore, as of February 24, 2003, have pathway and are not including it in this specified for the other laboratory
at least 2 years of training or experience, final rule. Although high complexity personnel categories described in
or both; and 2 years of experience procedures comprise less than 20 subpart M of the regulations.
directing or supervising high percent of the laboratory procedures Comment: Several commenters from
complexity testing. categorized, these are the most complex local, county, and public health officials
Comment: Several commenters tests requiring a broad-based knowledge in a State disagreed with the doctoral
(including one laboratory professional and the highest skills to fulfill the degree requirement and cited the State
organization and one certification director responsibilities (formerly at Code that allows an individual with a
board) felt continuing education should § 493.1445) and ensure quality testing. baccalaureate or master’s degree to
be added as a requirement to the second Therefore, we believe the knowledge direct a public health laboratory. The
proposed provision. and training of a high complexity commenters noted that although the
Response: We acknowledge that laboratory director with a doctoral public health laboratories currently
continuing education is important; degree can best be demonstrated have a director who meets the CLIA
however, the proposed rule did not through board certification. In addition, regulations, many of these directors
include a continuing education in the former regulations, we provided qualified under the former regulations at
component for this provision. In phase-in qualification requirements that § 493.1443(b)(5), the ‘‘grandfather’’
addition, when ‘‘grandfathering’’ allow individuals with a doctoral degree provision that qualifies individuals if on
individuals who are serving or who to qualify based on training and or before February 28, 1992, they were
have served in a particular position, experience in lieu of board certification qualified as a director under State law.
minimum qualification requirements are until the specified expiration date. As Many of these directors will retire
considered so as not to disenfranchise mentioned earlier, on five separate within 5 years.
these individuals. Finally, while occasions, we extended the phase-in Response: For the reasons stated
regulations specify minimum provision to allow time for directors previously, we believe the education
requirements, States, accreditation who were not board certified to requirements for directors of high
organizations, and certification boards complete the certification requirements complexity laboratories are appropriate
may establish more stringent and for HHS to review and approve and should not be lowered. In addition,
requirements. certification boards. During the 10 years as noted by the commenters, the
Comment: The majority of the the phase-in provision has been in February 28, 1992 final rule with
commenters were opposed to including affect, HHS has approved five additional comment period included a grandfather
the third provision (at proposed boards and we believe sufficient time provision that qualified individuals that
§ 493.1443(b)(3)(iii)). While there was has been provided for individuals to were serving as laboratory directors
general agreement that training and become aware of the board certification under State law on or before that date.
experience is essential for direction of requirement. Moreover, recent efforts of We also provided a phase-in provision,
high complexity testing, a few certification boards have provided which allows individuals with doctoral
commenters (including a certification additional routes to certification, degrees time to obtain board
board and a laboratory professional allowing more individuals to meet the certification by the specified expiration
organization) noted that training and certification requirements. date. The phase-in provision was
experience vary greatly and it would be In this final rule, board certification extended on multiple occasions and
inappropriate to use training and will be required for an individual with during this 10-year period HHS has
experience as sole criteria to qualify a doctoral degree seeking to become a approved five additional boards. We
individuals with a doctoral degree to high complexity laboratory director on believe sufficient time has been
direct high complexity testing. CLIAC and after February 24, 2003. However, provided for individuals to become
also recommended that this provision as previously mentioned, we are aware of the requirements. In this
be eliminated because it would not allowing individuals, who qualified regard, the State revised its statutes in
provide adequate documentation of the under the phase-in provision and are a February 18, 1998 amendment and
knowledge and skills needed for now serving or have served as directors now requires any city or county public
directorship of high complexity testing, of laboratories performing high health laboratory and its personnel to
lacks a mechanism to ensure continued complexity testing, to continue to serve comply with the CLIA regulations.
competency, and is not commensurate as laboratory directors. Comment: One commenter thought
with the high complexity laboratory Comment: A few commenters the proposed regulation would only
director responsibilities. Several disagreed with requiring a doctoral allow physicians to serve as directors of
commenters noted that this proposed degree as the minimum education laboratories performing high complexity
qualification pathway might result in an requirement for directors of laboratories testing.
Response: Although physicians with highly complex and requires specialized Response: We agree with the
certain training or experience are skills for direction, other specialty areas commenter. A requirement already
qualified to serve as directors of (for example, cytogenetics and appears at §§ 493.1407(e)(5) and
laboratories performing high complexity pathology) are also complex and require 493.1445(e)(5), moderate complexity
testing, the notice of proposed specialized technical expertise. Under and high complexity laboratory director
rulemaking only included proposed the CLIA regulations, the requirements responsibilities, respectively, and states
revisions to the qualification for specialty training and experience are ‘‘The laboratory director must ensure
requirements by which an individual included under the qualification that the quality control and quality
with a doctoral degree may serve as a requirements for the technical assessment programs are established
director of a laboratory that performs supervisor, which vary depending on and maintained to ensure the quality of
high complexity testing. the specialty of service. The December laboratory services provided and to
Comment: We received numerous 28, 2001 proposed regulation did not identify failures in quality as they
comments on the qualification include technical supervisor occur.’’ In addition, we are now
requirements for directors of requirements, and we are not making providing an introduction at § 493.1200,
laboratories performing any changes to the former requirements subpart K that provides an overview of
histocompatibility testing. The majority for technical supervisors. what quality systems include, the
of this group of commenters, which In addition, several commenters importance of ongoing assessment of
included the American Society of mistakenly thought that having the these systems, and the laboratory’s
Histocompatibility and Immunogenetics director meet the histocompatibility responsibility for establishment and
(ASHI), and the American Board of technical supervisor requirements maintenance of appropriate policies and
Histocompatibility and Immunogenetics would eliminate the need for two procedures. The term ‘‘quality
(ABHI), were in support of requiring individuals. Two individuals are only assurance’’ is synonymous with the
specific histocompatibility training and needed when a particular individual is term ‘‘quality assessment.’’ In addition,
experience for directors of laboratories unable to meet both the laboratory we are also making conforming changes
performing histocompatibility testing. director and histocompatibility (‘‘assessment’’ replaces ‘‘assurance’’)
Specifically, they were in favor of technical supervisor qualification where appropriate.
requiring individuals with a doctoral requirements. Comment: One commenter suggested
degree to either meet the Finally, while regulations specify the adding text at § 493.1709, Comparison
histocompatibility technical supervisor minimum requirements for compliance, of test results, that would acknowledge
requirements specified in the former accreditation organizations may the role the manufacturer may have in
regulations at § 493.1449(o) and be establish higher requirements for verifying the accuracy and reliability of
certified by ABHI; or be serving or have laboratory accreditation. test results at least twice a year. Other
served as a director of a Subpart P—Quality Assurance for commenters suggested language to
histocompatibility laboratory and meet Moderate Complexity (Including the clarify that tests not included under
the histocompatibility technical Subcategory), High Complexity Testing,
subpart I, performed by the laboratory at
supervisor requirements at various (multiple) testing sites, must
or Any Combination of These Tests
§ 493.1449(o). Opposing comments also be evaluated twice a year.
expressed concern that ASHI’s proposal Following publication of the February Response: Manufacturers are not
would exclude qualified individuals 28, 1992 final rule with comment precluded from providing services to
currently serving as directors of period, we received approximately 25 laboratories to assist in verification of
laboratories performing comments in reference to subpart P. The the accuracy and reliability of test
histocompatibility testing and is comments were in response to the procedures. However, it is ultimately
unnecessarily restrictive in an effort to requirements for enforcement of a the responsibility of the laboratory to
protect the employment of those written quality assurance policy. The develop and implement protocols for
individuals who possess ABHI laboratory’s policy was required to the biannual evaluation and comparison
certification. address the ongoing and overall of test results obtained using the
Response: We do not agree that the monitoring and evaluation of the quality different methodologies and
qualifications for directors of of the total testing process and the instruments employed by the laboratory
laboratories performing laboratory’s policies and procedures, and various testing sites the laboratory
histocompatibility testing, which is identifying and correcting problems to may have (for example, central
categorized as high complexity testing, ensure the accurate, reliable, and laboratory, satellite laboratories, point-
need to be revised to include specific prompt reporting of test results, and to of-care testing). In addition, the
histocompatibility training and ensure the adequacy and competency of laboratory must, twice a year, verify the
education requirements. We note the the staff. Over half of the comments accuracy of any test it performs that is
revisions suggested by ASHI would received agreed with most of the not listed in subpart I. Therefore, we
establish higher director qualification requirements. Approximately 25 percent believe the requirements, formerly at
requirements for individuals having a of the comments disagreed with some of § 493.1709 (now at §§ 493.1281 and
doctoral degree than for physicians who the requirements or offered specific 493.1236), clearly state the testing that
direct laboratories performing revised language. must be evaluated and the requirements
histocompatibility testing. In addition, Specific comments and responses remain unchanged.
these suggested changes to the regarding subpart P are set forth below. Comment: We received a comment
qualifications for directors of Comment: One commenter suggested agreeing with the requirement at
laboratories performing that the CLIA regulation specify who § 493.1707, Proficiency testing
histocompatibility testing would be has primary responsibility for QA assessment. The commenter stated that
inconsistent with the former activities by adding a statement, for all proficiency testing (PT) results that
qualifications required to direct example, ‘‘The laboratory director is were not correct should be investigated.
laboratories performing other testing responsible for ensuring that a quality Another commenter stated that all
specialties. Although the commenters assurance program is established and regulated analytes must be graded or the
maintained that histocompatibility is maintained.’’ PT program must notify HHS and the
affected laboratory of any challenge, however, there are reasons why false tests,’’ and adding, in their place, the
analyte, or test method for which it grading occurs. Almost all areas of words ‘‘nonwaived testing.’’
cannot produce a grade and the reasons testing under PT must be graded on an • We revised § 493.45 by removing
why grading is not possible. A few overall basis, that is, each analyte score the reference to ‘‘subpart P.’’
commenters strongly disagreed with the under a subspecialty or specialty is • We revised § 493.47 by removing
practice of assigning a 100 percent score averaged on each testing event to the reference to ‘‘subpart P’’.
to PT analytes when the laboratory has provide the laboratory with an overall • We revised § 493.47(c)(3) by
not earned the score. The commenters subspecialty or overall specialty score. removing the cross reference to
stated that this practice penalizes In order to determine an overall score, ‘‘§ 493.1776’’ and adding, in its place, a
laboratories that have correctly each analyte must receive a numerical cross reference to ‘‘§§ 493.1773’’ and
performed testing on all PT samples and score to allow the overall specialty or ‘‘493.1775.’’
causes laboratories that receive false subspecialty to be graded. The • We revised § 493.49 by removing
representation of a grade to believe their circumstances that a PT program may the reference to ‘‘subpart P.’’
test performance is exemplary, when it assign an analyte score that does not Subpart F—General Administration
has not been comparatively evaluated. reflect the laboratory’s true test
Additionally, laboratory testing performance include: (1) Analyte • We added at § 493.643(c)(3)(ix) the
problems that exist are not identified; evaluation does not produce at least 90 word ‘‘Clinical before the word
therefore, no corrective actions are percent agreement among participant or ‘‘Cytogenetics’’ to correct a technical
taken. referee laboratories that is required by error. The word was inadvertently
Response: Individual responses to the regulation (the laboratory receives 100 omitted from the final rule with
above comments are as follows: percent score); (2) laboratory did not comment period.
• We agree with the commenter and participate in the testing event (the
are retaining the requirement formerly Subpart H—Participation In Proficiency
laboratory receives zero percent score); Testing for Laboratories Performing
at § 493.1707 (now at § 493.1236) for the or (3) laboratory’s PT results were
laboratory to review and evaluate results Nonwaived Testing
received after the cut-off date for receipt
obtained on proficiency testing. PT (the laboratory receives a score of zero • We revised the heading of subpart
result review is part of the QA process. percent for the late return of results). In H to read ‘‘Participation In Proficiency
• We anticipate all regulated analytes Testing for Laboratories Performing
response to the commenters’ concerns,
(those listed in subpart I) will be graded Nonwaived Testing.’’
we are now requiring at § 493.1236(a)(2)
by approved PT programs. The
that the laboratory verify the accuracy of • We revised ‘‘§ 493.801(a)(2)(ii)’’ by
commenter is correct that, in some removing the cross reference to
the analytes for which a grade was
cases, not all challenges have been ‘‘§ 493.1709’’ and adding, in its place,
assigned that did not reflect its true
graded. Occasionally, as new ‘‘§ 493.1236(c)(1).’’
testing performance.
methodologies or new instrumentation • We revised ‘‘§ 493.803(a)’’ by
are developed for tests listed in subpart V. Provisions of the Final Rule removing the words ‘‘tests of moderate
I, PT material is not always available or In response to public comments on complexity (including the subcategory),
compatible with the new methods or the final rule with comment period and and/or high complexity’’ and adding, in
instruments. In order to ensure that to provide policy clarifications, we their place, the words ‘‘nonwaived
laboratories using new methodologies or made a number of changes in this final testing.’’
instruments evaluate their performance, rule, which are summarized as follows: • We revised the heading of § 493.807
we are (now at § 493.1236(c)(2)) to read ‘‘Condition: Reinstatement of
requiring laboratories to verify twice Subpart A—General Provisions laboratories performing nonwaived
annually the accuracy of tests listed in (Definitions) testing.’’
subpart I for which compatible PT • We added at § 493.2 the definitions
material is not available from approved Subpart I—Proficiency Testing
for the terms ‘‘calibration,’’ ‘‘calibration Programs for Nonwaived Testing
programs. verification,’’ ‘‘FDA-cleared or approved
• We agree with the commenter’s test system,’’ ‘‘reportable range,’’ and • We revised the heading of subpart
recommendation to require PT programs ‘‘test system.’’ I to read ‘‘Proficiency Testing Programs
to notify the laboratories and HHS of • We revised § 493.3(b)(3) to remove for Nonwaived Testing.’’
any challenge, analyte, or test method the words ‘‘National Institutes on Drug • We revised this subpart by changing
that cannot produce a grade and the Abuse (NIDA)’’ and add, in their place, the 90 percent consensus requirement to
reasons why grading is not possible. As the agency’s new name, ‘‘Substance 80 percent consensus.
CDC and CMS perform the annual Abuse and Mental Health Services • We revised § 493.945 by removing
review of PT programs required by the Administration (SAMHSA).’’ the cross reference to ‘‘§ 493.1257’’ and
CLIA statute, programs must submit an • We revised § 493.20 by removing adding in its place
annual report and, if needed, an interim the reference to ‘‘subpart P’’ and adding §§ 493.1105(a)(7)(i)(A) and
report that identifies any previously the cross reference to ‘‘§ 493.1773.’’ 493.1274(f)(2).’’
unrecognized sources of variability in • We revised § 493.25 by removing Revisions to Subpart J and K
kits, instruments, methods, or PT the reference to ‘‘subpart P’’ and adding
samples that adversely affect the the cross reference to ‘‘§ 493.1773.’’ As stated in section II of this preamble
programs’ ability to evaluate laboratory (Highlights and Organization of Final
performance. This requires PT programs Subpart C—Registration Certificate, Rule), we have consolidated and
to report problems to CMS. We are also Certificate for Provider-performed reorganized the requirements formerly
requiring programs to notify laboratories Microscopy Procedures, and Certificate in Subpart J—Patient Test Management
(on the laboratory’s PT results report) of of Compliance for Moderate Complexity (Including the
exceptions and/or problems that • We revised § 493.43(a) by removing Subcategory), High Complexity, or Any
precluded an analyte from being graded. the words ‘‘tests of moderate complexity Combination of These Tests, Subpart
• We appreciate the commenters’ (including the subcategory) or high K—Quality Control for Tests of
concerns regarding false grading; complexity, or any combination of these Moderate Complexity (Including the
Subcategory), High Complexity, or Any to specify the record retention • We removed the requirement
Combination of These Tests, and requirements for immunohematology formerly at § 493.1217(b)(2)(ii)(B)(1)
Subpart P—Quality Assurance for and blood and blood products to ensure (calibration verification requirement)
Moderate Complexity (Including the consistency with the FDA requirements. regarding use of calibration materials
Subcategory) or High Complexity • We revised the requirement now at traceable to a reference method or
Testing, or Any Combination of These § 493.1105(a)(6) (formerly § 493.1109 reference material of known value to
Tests, into a new Subpart J—Facility introductory text) to remove the words allow flexibility in choosing material for
Administration for Nonwaived Testing, ‘‘exact duplicate’’ and specify that the calibration verification.
and Subpart K—Quality Systems for laboratory must be able to retrieve a • We removed the requirements
Nonwaived Testing. Below, we have copy of the original report. formerly at § 493.1225, the Condition of
only set forth substantive revisions to Microbiology, as it is a duplicate of the
Subpart K—Quality Systems for requirements under the Conditions of
subparts J and K.
Nonwaived Testing Bacteriology, Mycobacteriology,
Subpart J—Facility Administration for
• We revised the heading of subpart Mycology, Parasitology, and Virology,
Nonwaived Testing now at §§ 493.1201, 493.1202, 493.1203,
K to read ‘‘Quality Systems for
• We revised the heading of subpart Nonwaived Testing.’’ 493.1204, and 493.1205, respectively.
J to read Facility Administration for • We revised subpart K to consist of • We clarified the requirement now at
Nonwaived Testing. §§ 493.1200 through 493.1299. § 493.1236 (formerly at § 493.1707) that
• We revised subpart J to consist of • We revised the introductory text laboratories must verify the accuracy of
§§ 493.1100 through 493.1105. now at § 493.1200 to provide an any analyte, specialty, or subspecialty
• We specified now at § 493.1100 that overview of quality systems, including when it is assigned a proficiency testing
laboratories performing nonwaived the importance of ongoing assessment of score that does not reflect laboratory test
testing must meet the applicable these systems, and the laboratory’s performance.
standard level requirements in responsibility for establishment and • We added the requirement now at
§§ 493.1101 through 493.1105. maintenance of appropriate policies and § 493.1236(c)(2) that laboratories verify
• We added the requirement now at procedures. twice annually the accuracy of tests
§ 493.1101(c) that laboratories must • We removed the lead-in paragraph listed in subpart I for which compatible
comply with Federal, State, and local formerly at § 493.1201(a) explaining the PT material is not available from
requirements concerning laboratories division between general QC and the QC approved PT programs.
and ensure that adequate safety • We removed the requirement
for the specialties and subspecialties.
precautions are in place to provide formerly at § 493.1237, the Condition of
• We removed the requirement
protection from laboratory hazards. Diagnostic Immunology, as it is a
formerly at § 493.1201(a)(1) regarding
• We revised the language now at duplicate of the requirements under the
the clearance process for alternative QC
§ 493.1101(d) (formerly at § 493.1204(b)) Conditions of Syphilis Serology and
procedures that were never established
requiring safety procedures to be General Immunology now at
by the FDA.
accessible rather than posted. §§ 493.1207 and 493.1208, respectively.
• We clarified the record keeping • We removed the requirement • We revised the language now at
requirements now at § 493.1101(e) for formerly at § 493.1203 regarding the § 493.1241(b) (formerly at § 493.1105) to
laboratories to store and maintain clearance process for moderate clarify that an oral request for laboratory
records in a manner that ensures proper complexity testing. tests is permitted only if laboratory
preservation. This clarification applies • We redesignated the requirement requests written or electronic
to the requirements now at § 493.1771(c) formerly at § 493.1205 regarding test authorization for testing within 30 days
and (d), and former §§ 493.1105, methods, equipment, instrumentation, of the oral request and documents the
493.1107, and 493.1221 introductory reagents, materials, and supplies. We efforts made to obtain a written or
text. incorporated the majority of these electronic authorization.
• We removed the language formerly provisions into § 493.1252. The • We revised the language now at
at § 493.1103(c) regarding laboratories requirements formerly at § 493.1205(b) § 493.1241(c)(3) (formerly at
providing oral instruction to patients as are now at § 493.1101(b) and the § 493.1105(e) and (f)) to specify that the
a supplement to written instructions, biologic product dating requirements test requisition must solicit the patient’s
when appropriate. formerly at § 493.1205(e) are now at sex and age or date of birth.
• We clarified the requirement now at § 493.1271(b). • We added the requirement now at
§ 493.1103(d) (formerly at § 493.1271) • We removed the requirement § 493.1241(c)(5) (formerly § 493.1105(f))
that the facility must report transfusion formerly at § 493.1213(b)(1) regarding that the laboratory must ensure that the
reactions to the laboratories and, as the QC clearance process for the test requisition solicits the source of the
appropriate, to Federal and State manufacturer’s process for verification specimen when appropriate.
authorities. of performance specifications for new • We revised the language now at
• We revised the language now at patient testing devices introduced by § 493.1241(c)(7) (formerly at
§ 493.1105(a)(3)(i) (formerly at the laboratory. § 493.1105(e)) removing the age or date
§ 493.1221) to specify that the laboratory • We removed the requirement of birth requirement for Pap smear
must retain records of test system formerly at § 493.1215(a)(1) regarding requisitions because it is now a
performance specifications that the the CLIA QC clearance process for requirement for all test requisitions at
laboratory establishes or verifies under maintenance of equipment, instruments, § 493.1241(c)(3).
§ 493.1253 for the period of time the and test systems. • We revised the requirement now at
laboratory uses the test system but no • We removed the requirement § 493.1241(e) (formerly § 493.1701) to
less than 2 years. formerly at § 493.1217(a) regarding the provide clarification that if the
• We revised the language now at CLIA QC clearance process for use of laboratory transcribes or enters test
§ 493.1105(a)(3)(ii) (formerly § 493.1107 the manufacturer’s instructions for requisition or authorization information
introductory text) and § 493.1105(a)(6)(i) calibration and calibration verification into a record system or laboratory
(formerly § 493.1109 introductory text) procedures. information system, the laboratory must
ensure that the information is • We removed the requirement • We revised the requirement now at
transcribed or entered accurately. formerly at § 493.1255, the Condition of § 493.1261 by incorporating the
• We revised the requirement now at Pathology, as it is a duplicate bacteriology requirements formerly at
§ 493.1242(a)(3) (formerly § 493.1105(f)) requirement under the Conditions of § 493.1227.
clarifying that the specimen source Histopathology, Oral Pathology and • We revised the language now at
requirement, when appropriate, is part Cytology now at §§ 493.1219, 493.1220, § 493.1261 (formerly § 493.1227),
of the laboratory’s submission, and 493.1221, respectively. reducing the requirements by removing
handling, and referral procedures. • We revised the language now at the reference to specific control
• We removed the requirement § 493.1256 by removing the mandatory requirements in the subspecialty of
formerly at § 493.1243, the Condition of concurrent control testing requirements bacteriology.
Chemistry, as it is a duplicate formerly at §§ 493.1237 Diagnostic • We revised the requirement now at
requirement under the Conditions of immunology; 493.1239 Syphilis § 493.1262 by incorporating the
Routine Chemistry at § 493.1210, serology; and 493.1241 General mycobacteriology requirements formerly
Urinalysis at § 493.1211, Endocrinology immunology. We now require two levels at § 493.1229.
at § 493.1212, and Toxicology at of QC materials once each day of testing. • We added a requirement in
§ 493.1213. • We revised the language now at mycobacteriology now at § 493.1262(a)
• We clarified the requirement now at § 493.1256(d) (formerly at § 493.1218(b)) (formerly § 493.1229(a)) for an acid fast
§ 493.1251(b)(13) (formerly at reducing the requirement by removing control organism that produces a
§ 493.1211(b)(14)) that the procedure the specialty-specific control negative reaction.
manual must include in the test requirements (formerly at § 493.1253(b)) • We revised the requirement now at
procedure the laboratory’s system for for automated hematology analyzers. We § 493.1263 by incorporating the
entering results in the patient record now require two levels of control mycology requirements formerly at
and reporting patient results including materials once each day of testing. § 493.1231.
the protocol for reporting panic or alert • We revised the language now at • We revised the requirement now at
values, when appropriate. § 493.1256(d)(3) (formerly at § 493.1263(a) (formerly at
• We revised the language now at § 493.1218(b)) to clarify that QC § 493.1218(f)(2)). We reduced the
§ 493.1251(d) (formerly at § 493.1211(d)) materials are assayed or examined each requirement to QC certain staining
to provide that procedures and changes day of patient testing. materials each day of use to only
checking each batch, lot number, and
in procedures must be approved, signed, • We revised the requirement now at
and dated by the current laboratory shipment of lactophenol cotton blue
§ 493.1256(d)(3) for hematology by
director before use. when prepared or opened for intended
reducing the required frequency for
reactivity.
• We revised the language now at control testing (formerly at
• We revised the requirement now at
§ 493.1252(b) (formerly § 493.1253(b)) from once each 8 hours of
§ 493.1263(b) (formerly § 493.1213(d))
§§ 493.1202(c)(1) and 493.1205(c)) to operation to once each day of testing.
by reducing the requirement for daily
specify that the laboratory’s criteria for • We added the requirement now at
testing to merely testing each batch of
storage of reagents and specimens and § 493.1256(d)(3)(v) that the laboratory
media and each lot number and
test system operations must be must use a control system capable of
shipment of antifungal agents before or
consistent with the manufacturer’s detecting reaction inhibition when
concurrent with initial use.
instructions, when available. performing molecular amplification • We revised the requirement now at
• We revised the language now at procedures in which inhibition is a § 493.1264 by incorporating the
§ 493.1253(a) (formerly at § 493.1213(a)) significant source of false negative parasitology requirements formerly at
to provide that laboratories are not results. § 493.1233.
required to verify or establish • We removed the term ‘‘drug abuse • We revised the requirement now at
performance specifications for any test screening’’ at § 493.1256(d)(4)(i), and § 493.1265 by incorporating the virology
system used by the laboratory before added the term ‘‘all known substances requirements formerly at § 493.1235.
April 24, 2003. or drug groups’’ identified and reported • We removed the requirement
• We revised the language now at by the laboratory to accommodate the formerly at § 493.1265(a)(10) that
§ 493.1253(b)(1) (formerly at wider use of the technology. required the laboratory to use specific
§ 493.1213(b)(2)) by adding the words • We revised the language now at techniques such as mixed lymphocyte
‘‘FDA-cleared or approved test system’’ § 493.1256(d)(5) (formerly at cultures to determine HLA Class II
to the requirements regarding § 493.1218(b)(3)) to clarify that the incompatibilities.
verification of performance laboratory must for each electrophoretic • We removed the requirement
specifications. procedure, include, concurrent with formerly at § 493.1265(a)(13) that
• We revised the heading now at patient specimens, at least one control required histocompatibility testing
§ 493.1254 (formerly § 493.1215) to read material containing the substances being personnel to evaluate unknowns on a
‘‘Maintenance and function checks.’’ identified or measured. monthly basis because it is duplicative
• We revised the language now at • We revised the language now at of the laboratory director
§ 493.1254(a)(2) (formerly at § 493.1256(e)(2) (formerly responsibilities at § 493.1445(e).
§ 493.1215(b)(2)(ii)) regarding function § 493.1218(f)(2)) to clarify the use of • We revised the requirement now at
checks by removing the word staining materials. § 493.1267 by incorporating the routine
‘‘laboratory’’ and adding, in its place, • We clarified the use of calibration chemistry requirements formerly at
the word ‘‘manufacturers.’’ materials now at § 493.1256(d)(9) § 493.1245.
• We clarified the requirement now at (formerly at § 493.1218(h)(2)) to provide • We revised the language now at
§ 493.1254(a)(2) (formerly at that calibration material used as a § 493.1267(b) (formerly at §§ 493.1245(c)
§§ 493.1202(c)(1) and 493.1215(b)(2)(ii)) control material must be from a different and (d)) by removing reference to the
to require that function checks be lot number than that used to establish words ‘‘calibration and calibration
within the manufacturer’s established a cut-off value or to calibrate the test material’’ from the blood gas
limits before conducting patient testing. system. requirements. However, we allow
calibration material as a control material document that the resolution used was • We revised the requirement now at
provided it is from a different lot appropriate for the type of tissue or § 493.1278(f)(1) (formerly at
number than that used to calibrate the specimen, and the type of study § 493.1265(b) and (c)) that requires
test system or establish a cut-off. required based on the clinical specific testing protocols to be less
• We revised the requirements now at information provided to the laboratory. prescriptive and allow laboratories to
§ 493.1269 by incorporating the • We revised the language now at define testing policies and protocols for
hematology requirements formerly at § 493.1276(c) (formerly at § 493.1267(a)) each type of cell, tissue, or organ to be
§ 493.1253. by removing the requirements transfused or transplanted.
• We revised the requirement now at pertaining to the performance of X and • We clarified the requirement now at
§ 493.1271 by incorporating the Y chromatin counts for sex § 493.1278(f)(3) (formerly at
immunohematology requirements determination and requiring full § 493.1265(b)(3)) that the laboratory
formerly at §§ 493.1239(e), 493.1241(d), chromosome analysis for sex must have available, and follow,
493.1269, 493.1273, 493.1275, 493.1283, determination. policies that address when HLA testing
and 493.1285. • We revised the language now at and final crossmatches are required for
• We revised the requirement now at § 493.1276(d) (formerly at § 493.1267(d)) presensitized non-renal transplant
§§ 493.1271(a)(1) and (b) (formerly by removing the reference to the words recipients.
§§ 493.1269(a) and 493.1273) to cite the ‘‘appropriate nomenclature’’ and • We clarified the requirements now
specific 21 CFR requirements that must specifying that the laboratory report at § 493.1291(a) (formerly at
be met under the CLIA regulations. must use the International System of § 493.1109(a)) to provide that the
• We revised the requirement now at Cytogenetic Nomenclature. laboratory must have adequate systems
§ 493.1273 by incorporating the • We revised the requirement now at in place to ensure test results and other
histopathology requirements formerly at § 493.1278 by incorporating the patient specific data are accurately and
§ 493.1259. histocompatibilty requirements formerly reliably transmitted from the point of
• We added a requirement at at § 493.1265. data entry (whether interfaced or
§ 493.1273(a) (formerly at § 493.1259) • We added the requirement now at entered manually) to final report
that the laboratory must check § 493.1278(a)(3) that reagent specificity destination, in a timely manner.
immunohistochemical stains for is required when reagent typing sera • We clarified the requirement at
positive and negative reactivity each inventory is prepared in-house. § 493.1291(c)(3) (formerly at §§ 493.1109
time of use in order to be consistent • We added requirements now at and 493.1109(a)) to specify that the date
with the general QC requirements at § 493.1278(b)(1) that the laboratory must of the test report must be identified on
§ 493.1256(e)(3). use a technique that is established to the report.
• We revised the language now at optimally define, as applicable, HLA • We clarified the requirement now at
§ 493.1273(c) (formerly at § 493.1259(b)) Class I and II specificity. § 493.1291(c)(5) (formerly at § 493.1109)
to add that an individual who has • We added requirements at to indicate that the test report must
successfully completed a training § 493.1278(d)(1) and (d)(2) to specify include the specimen source, if
program in neuromuscular pathology that the laboratory must use a technique applicable.
approved by HHS may examine and that detects HLA specific antibody with • We added language relevant to
provide reports for neuromuscular a specificity equivalent or superior to interpretation to the test report
pathology. that of the basic complement-dependent requirements now at § 493.1291(c)(6)
• We revised the requirement now at microlymphocytotoxicity assay, and use (formerly § 493.1109(b)) for those test
§ 493.1274 by incorporating the cytology a method that distinguishes antibodies results that require supplemental
requirements formerly at § 493.1257. to HLA class II antigens from antibodies information.
• We revised the language now at to Class I antigens. • We revised the language now at
§ 493.1274(d)(2)(iii) (formerly at • We revised the language now at § 493.1291(j) (formerly § 493.1109(h)) by
§ 493.1257(b)(2)) by removing the § 493.1278(d)(4) and (d)(5) (formerly at removing the words ‘‘exact duplicate’’
reference to gynecologic slides from the 493.1265(a)(2)(ii) and (a)(8)(i)) to require and clarified the language by specifying
200-workload limit that applies only to laboratories to make a reasonable that all test reports or records of the
nongynecologic slides. attempt to have available monthly information on the test reports must be
• We revised the language now at serum specimens for periodic antibody maintained by the laboratory in a
§ 493.1274(e)(1) (formerly at screening and crossmatch, and have manner that permits ready identification
493.1257(c)(1)) by removing the available and follow a written policy and timely accessibility.
requirement that a technical supervisor consistent with clinical transplant
review cases categorized as reactive and protocols for the frequency of Subpart M—Personnel for Nonwaived
reparative changes. performing antibody screening. Testing
• We revised the requirement now at • We added the requirement now at • We revised the heading of subpart
§ 493.1276 (formerly at § 493.1267) by § 493.1278(d)(7) to specify that for M to read ‘‘Personnel for Nonwaived
incorporating the clinical cytogenetics antibody screening, the laboratory must, Testing’’ to conform with the names of
requirements. as applicable, have available, and follow the new subparts J and K.
• We clarified the requirement at criteria and procedures for antibody • We revised § 493.1359(a)(3) by
§ 493.1276(a) (formerly §§ 493.1107 and identification to the level appropriate to removing the reference to ‘‘subpart P.’’
493.1267(c)) by specifying that the support clinical transplant protocol. • We revised § 493.1407(e)(5) by
laboratory must have policies and • We revised the language now at removing the word ‘‘assurance’’ and,
procedures for ensuring accurate and § 493.1278(e)(1) (formerly adding in its place, the word
reliable patient specimen identification § 493.1265(a)(1)(ii) to clarify that the ‘‘assessment.’’
for karyotypes. techniques for crossmatching must be • We revised § 493.1443(b)(3) to
• We revised the requirement now at documented to have increased allow individuals with a doctoral degree
§ 493.1276(b)(2) (formerly at sensitivity in comparison to the basic who are serving or have served as
§ 493.1267(b)) to specify that the complement-dependent directors of laboratories performing high
laboratory must have records that microlymphocytoxicity assay. complexity testing before February 24,
2003, under the phase-in provision, to • Recommendations to minimize the collection requirement is subject to the
continue to qualify as directors of information collection burden on the PRA, we believe the burden is exempt
laboratories performing high complexity affected public, including automated as defined in 5 CFR 1320.3(b)(2) because
testing. collection techniques. the time, effort, and financial resources
• We revised the requirement at We are soliciting public comment on necessary to comply with the
§ 493.1443(b)(3)(i) by removing the list each of these issues for the sections that requirement are incurred by persons in
of HHS-approved boards. We are contain new information collection the normal course of their activities.
placing the list in Appendix C of the requirements. Except as indicated
Section 493.1242 Standard: Specimen
State Operation Manual (CMS Pub. 7) to below, all of the information collection
Submission, Handling, and Referral
allow more timely updates. burden in this final rule has been
• We revised § 493.1445(e)(5) to refer approved by the OMB under approval At paragraph (a), we are clarifying the
to the quality assessment program. number 0938–0612 through June 2004. requirement, formerly at § 493.1103(a),
• We revised § 493.1451(c)(4) by Because the sections in this final rule that the laboratory’s written policies and
removing the reference to § 493.1257(c) are a reorganization of former sections, procedures for specimen labeling
and adding, in its place § 493.1274(d) the burden approval numbers cited state specify that the patient’s name or
and (e). the best approximation we could make unique patient identifier, and when
• We revised § 493.1471(b)(2) and for which combinations of former appropriate, specimen source be on the
§ 493.1485(a) by removing burden numbers match with the specimen label. This revision does not
‘‘§ 493.1257(d),’’ and adding, in its sections as specified in this final rule. add additional reporting burden for this
place, ‘‘§ 493.1274(c).’’ Our approximations are as follows: requirement under OMB approval
number 0938–0612.
Removal of Subpart P Section 493.1105 Standard: Retention
As stated in section II of this preamble Requirements Section 493.1251 Standard: Procedure
(Highlights and Organization of Final Under paragraph (a)(6), Test reports, Manual
Rule), we incorporated the former the laboratory must retain or be able to Paragraph (b)(13) requires that the
‘‘Subpart P—Quality Assurance; retrieve a copy of the original report procedure manual include the
Moderate Complexity (Including the (including final, preliminary, and laboratory’s system for entering results
Subcategory) or High Complexity corrected reports) at least 2 years after in the patient record and reporting
Testing, or Any Combination of These the date of reporting. patient results including, when
Tests’’ under the appropriate sections The change in this paragraph is that appropriate, the protocol for reporting
now located in Subpart K, General now the laboratory has the option of ‘‘panic or alert values.’’
Laboratory Systems, Preanalytic either retaining a copy of the report or This requirement, formerly at
Systems, Analytic Systems, and having the capability of generating a § 493.1211(b)(14), now includes the
Postanalytic Systems. copy of the report. This revision does provision for a written procedure
not change the burden captured under describing the laboratory’s processes for
Subpart R—Enforcement Procedures OMB approval number 0938–0612. entering results into patient records.
• We revised § 493.1844 by removing This revision does not change the
the reference to ‘‘subpart P.’’ Section 493.1241 Standard: Test paperwork burden captured for this
Request requirement under OMB approval
Subpart T—Consultations At paragraph (c), the laboratory must number 0938–0612.
• We revised § 493.2001(e)(1) to read ensure that the written or electronic test
‘‘Criteria for categorizing nonwaived Section 493.1253 Standard:
requisition solicits the following:
testing.’’ • The sex and age or date of birth of Establishment and Verification of
• We revised § 493.2001(e)(4) to read the patient. Performance Specifications
‘‘Facility administration and quality • The source of the specimen, as Each laboratory that introduces an
systems standards;’’ appropriate. unmodified, FDA-cleared or approved
• The date and, if appropriate, time of test system must, before reporting
VI. Collection of Information specimen collection. patient test results, demonstrate that it
Requirements • Any additional information relevant can obtain performance specifications
Under the Paperwork Reduction Act and necessary to a specific test to ensure comparable to those established by the
(PRA) of 1995, we are required to accurate and timely testing, and manufacturer for the specified
provide 60-day notice in the Federal reporting of results, including performance characteristics.
Register and solicit public comment interpretation, if applicable. In addition, each laboratory that uses
before a collection of information is These new requirements mandate that a test system in which performance
submitted to the Office of Management laboratories solicit the sex and age or specifications are not provided by the
and Budget (OMB) for review and date of birth of the patient and, if manufacturer, modifies an FDA-cleared
approval. In order to fairly evaluate appropriate, the source of the specimen or approved test system or introduces a
whether an information collection and the time of specimen collection on test system not subject to FDA clearance
should be approved by OMB, section the test request. In addition, the or approval (includes standardized
3506(c)(2)(A) of the PRA requires that requirements clarify that the relevant methods and methods developed in-
we solicit comment on the following information needed to ensure accurate house) must, before reporting patient
issues: and timely testing and reporting of test results, establish for each test
• The need for the information results includes relevant information for system the performance specifications
collection and its usefulness in carrying interpretation of results. for specified performance
out the proper functions of our agency. We believe the burden of soliciting characteristics.
• The accuracy of our estimate of the this information is minimal, as it is Based upon the performance
information collection burden. routinely captured by laboratories as specifications verified or established,
• The quality, utility, and clarity of part of good business practices. the laboratory must determine
the information to be collected. Therefore, while this information calibration procedures and control
procedures. Also, the laboratory must There may be increased reporting for In paragraph (e)(3), the laboratory
have documentation of the laboratory’s unmodified moderate complexity tests must check fluorescent and
performance of all activities specified in (formerly at § 493.1202(c)) whose immunohistochemical stains for
this section. manufacturer’s instructions did not positive and negative reactivity each
This is a 2-part requirement and will include these requirements. The burden time of use. Therefore, reporting will
affect laboratories differently depending for the remainder of the tests is captured increase from one to two control results
on whether they are verifying or for this requirement under OMB in the subspecialty of histopathology for
establishing performance specifications approval number 0938–0612. tests performed using
for a test method. In addition, it only • In paragraph (d)(3)(iii), for each immunohistochemical stains. For
applies to new laboratories and new semiquantitative procedure, include a mycobacteriology, recording control
tests instituted in existing laboratories negative control material and, as results will increase from each week of
on and after April 24, 2003. Therefore, applicable, a control material with use to each time of use for fluorochrome
the number of laboratories needing to graded or titered reactivity. acid-fast stains. The burden of reporting
meet this requirement will be minimal. There will be an increase in one control result is captured for these
While this is a new requirement for paperwork burden for unmodified requirements under OMB approval
some laboratories performing testing moderate complexity tests (formerly at number 0938–0612.
using unmodified, moderate complexity § 493.1202(c)) whose manufacturer’s Under the former OMB approval, we
test systems approved or cleared by the instructions did not include this allotted 5 minutes per day for the
FDA, it only applies to tests newly requirement and for tests not subject to reporting requirements in the former
introduced into existing laboratories the specialty requirements formerly at § 493.1218. This time allotment was
and to all tests in laboratories first §§ 493.1239(b) or 493.1241(a). The based on the assumption that most of
established on or after April 24, 2003. In burden for the remainder of these tests the previously unregulated laboratories
addition, it is common practice for test for this requirement is captured under were performing moderate complexity
system manufacturers to perform or OMB approval number 0938–0612. testing and ran a total of four QC
• In paragraph (d)(3)(v), for each samples daily. This time allotted
provide extensive assistance with this
molecular amplification procedure, included reporting for the burden
quality control activity when a
include two control materials and, if associated with all the specialties and
laboratory buys or leases an instrument
reaction inhibition is a significant subspecialties; therefore, we believe the
or other new test system. Thus, in
source of false negative results, a control burden was slightly underestimated.
practice, most of the burden for
material capable of detecting inhibition. We are allotting 5 minutes per day to
recording and documenting the quality There will be increased burden for
control requirements are already born perform this documentation for the
recording the additional control results, specialties and subspecialties (except
by the test system manufacturers. We do when needed. The burden of recording
not believe that this burden will be bacteriology, mycobacteriology,
the former control results is captured for hematology, and histopathology) and
shifted to the laboratory. Also, this requirement under OMB approval
accrediting organizations and States are adjusting this burden to reflect the
number 0938–0612. number of laboratories currently
with licensure programs, after which the • In paragraph (d)(6), when a
CLIA requirements were modeled, have affected by this rule. We are addressing
complete change of reagents is the specialties and subspecialties of
traditionally required laboratories to introduced, major preventive
perform these activities. Therefore, bacteriology, mycobacteriology,
maintenance is performed, or any hematology, and histopathology
while this information collection critical part that may influence test
requirement is subject to the PRA, the separately. We are assuming laboratories
performance is replaced, the laboratory are documenting control activities on an
burden is exempt as defined in 5 CFR must, before resuming patient testing
1320.3(b)(2) because the time, effort, average of 6 days per week. Therefore,
perform control material testing as the burden for the specialties and
and financial resources necessary to specified under paragraph (d) of this
comply with the requirement are subspecialties (except bacteriology,
section. mycobacteriology, hematology and
incurred by persons in the normal There will be an increase in burden
course of their activities. histopathology) can be calculated as 5
for tests whose manufacturer’s min./day × 24 days/month = 120 min./
Section 493.1256 Control Procedures instructions did not include the month = 2 hrs./month 2 hrs./month × 12
requirements for control material testing months/yr. = 24 hours/laboratory/yr.
These requirements were previously specified under paragraph (d) of this The total estimated burden for this
at § 493.1218 and approved under OMB section. The burden for the remainder of requirement (now at § 493.1256) is
approval number 0938–0612. The the tests is captured for this requirement 27,685 laboratories (total number of
burden associated with these under OMB approval number 0938– laboratories minus the number of
requirements involves the 0612. waived laboratories, provider performed
documentation of the control results • Under paragraph (d)(10)(iii), when microscopy (PPM) laboratories, and
and corrective action taken when control materials providing quantitative previously regulated laboratories) × 24
control results do not meet the results are used, statistical parameters hrs./yr. = 664,440 hrs./yr.
laboratory’s acceptability criteria. for unassayed materials must be
Therefore, we are revising the established over time by the laboratory Section 493.1261 Standard:
paperwork requirements to some extent. through concurrent testing of control Bacteriology
Under paragraph (d), the laboratory materials having previously determined For the subspecialty of bacteriology,
must do the following, as applicable: statistical parameters. in this final rule at paragraph (a), the
• In paragraphs (d)(3)(i) and (ii), for There will be an increase in reporting laboratory must check the following for
each quantitative and qualitative for moderate complexity tests formerly positive and negative reactivity using
procedure, include two control subject to the phase-in at § 493.1202(c). control organisms:
materials of different concentrations and The burden for the remainder of these • Each day of use for beta-lactamase
a positive and negative control material, tests is captured under OMB approval methods other than Cefinase TM.
respectively. number 0938–0612. • Each week of use for Gram stains.
• When each batch (prepared in- Burden in This Final Rule and fluorochrome acid-fast stains is
house), lot number (commercially The estimated burden for 3,185 mycobacteriology laboratories ×
prepared), and shipment of antisera is documenting control testing for 0.8 hrs./yr. = 2,548 hrs./yr.
prepared or opened and once every 6 bacteriology reagents under this final The former total burden for
months thereafter. rule is 329,316 hrs./yr.—315,595 hrs./yr. documenting control testing for
In paragraph (b), for antimicrobial = 13,721 hrs./yr. mycobacteria identification reagents and
susceptibility tests, the laboratory must tests, and acid-fast, and fluorochrome
Section 493.1262 Standard: acid-fast stains was 3,651 hrs./year +
check each batch of media, lot number,
Mycobacteriology 2,548 hrs./year = 6,199 hrs/yr.
and shipment of antimicrobial agent(s)
before, or concurrent with, initial use, For the subspecialty of Change in Burden
using approved reference organisms mycobacteriology, in this final rule at
paragraph (a), each day of use, the Since documentation of the positive
and, each day tests are performed, the
laboratory must check all reagents or control reaction was previously required
appropriate control organisms must be
test procedures used for mycobacteria for mycobacteria identification reagents
used to check the procedure.
identification with at least one acid-fast and tests and the number of laboratories
Former Burden organism that produces a positive performing mycobacteriology remains
reaction and with an acid-fast organism constant, we also estimated the increase
In the former regulation, laboratories in burden for documenting the negative
that produces a negative reaction.
had to check catalase, coagulase, beta- control material for identification
lactamase, and oxidase reagents using a Former Burden reagents and tests to be one-half the
positive and negative control material In the former regulation, we included previous burden, which is 1⁄2 of 3,651
each day of use. In addition, the the requirements to document the hrs./yr. (from above) = 1,826 hrs./yr.
laboratories had to check bacitracin, results of control testing with the The change in burden for increasing
optochin, ONPG, XV, X, and V disks or general QC procedures. However, since the frequency of acid-fast and
strips using a positive and negative these documentation requirements are fluorochrome acid-fast stains to daily
control material each week of use. We now under the condition, Analytic and adding a negative acid-fast stain
estimate that most bacteriology systems at § 493.1250, we have removed result is calculated as 1.5 min/day × 26
laboratories operate an average of 6 days these documentation requirements from days/month = 39 min./month = 0.65
per week; therefore, we allowed an the general QC procedures and placed hrs./month × 12 months/yr. = 7.8 hrs./
average of 2.5 minutes per day to them in the subspecialty of laboratory/yr.
document the results of control testing mycobacteriology at § 493.1262. The total increase in burden for these
for the reagents listed above. This In the former regulation, the documentation requirements for acid-
resulted in the former burden, 2.5 min./ laboratory was required, each day of fast and fluorochrome acid-fast stains is
day × 24 days/month = 60 min./month use, to check all reagents or test 3,185 laboratories × 7.8 hrs./yr. = 24,843
= 1 hr./month 1 hr./month × 12 months/ procedures for mycobacteria hrs./yr.
year = 12 hrs./laboratory/yr. identification with an acid-fast positive The total increase in burden for
Under the former regulation, the control organism (except the iron uptake documenting control testing for
estimated burden for documenting test, which also requires a negative mycobacteria identification reagents and
control testing for the reagents above control). Assuming that only 35.4 tests, acid-fast, and fluorochrome acid-
was 27,443 bacteriology laboratories × percent (see section VII of this final rule, fast stains is 1,826 hrs./yr. + 24,843 hrs./
12 hrs./yr. = 329,316 hrs./yr. Regulatory Impact Analysis) of yr. = 26,669 hrs./yr.
mycobacteriology laboratories perform
Change in Burden Burden in This Final Rule
identification procedures, and test an
average of twice weekly, the former The total estimated burden under this
In this final rule, we are allowing
burden for documenting the positive final rule for documenting control
laboratories to check each batch, lot
control reaction for mycobacteria testing for mycobacteria identification
number and shipment of reagents
identification reagents and tests can be reagents and tests, acid-fast, and
(catalase, coagulase, and oxidase), disks
estimated as 2 min/day × 8 days/month fluorochrome acid-fast stains is 6,199
(bacitracin, optochin, ONPG, X, V, and
= 16 min./month = 0.27 hrs./month × 12 hrs./yr. + 26,669 hrs./yr. = 32,868 hrs./
XV), stains, antisera, and identification
months/yr. = 3.24 hrs./laboratory/yr. yr.
systems for positive and negative The total estimated burden for
reactivity, and graded reactivity if Section 493.1263 Standard: Mycology
documenting the positive control result
applicable. For purposes of calculating is 1,127 mycobacteriology laboratories × In the former regulation for mycology,
the burden, we are assuming that 3.24 hrs./yr. = 3,651 hrs./yr. each week of use, the laboratory was
laboratories receive a new shipment of As mentioned previously, the former required to check all procedures for
reagents on the average of once per regulation also required that the mycological identification (including
month. Since the burden with laboratory check positive and negative germ tube test) using an organism that
documenting control testing for control materials for fluorochrome acid- produces a positive reaction. Under this
susceptibility tests remain the same, we fast stains each week of use and check final rule, the requirement is eliminated.
are considering the burden for a positive control material for other This deletion results in the QC
documenting control testing for this acid-fast stains each week of use. The requirements for the germ tube test to
subspecialty to be reduced by 2.5 min./ former burden for all mycobacteriology default to the general QC requirements
day × 23 days/month = 57.5 min./month laboratories to document these control at § 493.1256(e)(1). The general
= 0.96 hrs./month 0.96 hrs./month × 12 results is estimated as 1 min/day × 4 requirements specify QC testing with
months/yr. = 11.5 hours/ laboratory/yr. days/month = 4 min./month × 12 each new batch, lot number or shipment
The total estimated reduction in months/yr. = 48 min./laboratory/yr. = of reagents. Because this is a minimal
burden for this requirement is 27,443 0.8 hrs./laboratory/yr. decrease (we estimate the change in
bacteriology laboratories × 11.5 hrs./yr. The total estimated burden for frequency from weekly to monthly) in
= 315,595 hrs./yr. documenting control testing for acid-fast burden for documenting the result of a
single control, we are unable to burden will be 2⁄3 of 275,880 hrs./yr. = Burden in This Final Rule
accurately estimate the change. 183,920 hrs/yr. The total estimated burden under this
Similarly, in paragraph (a), the In addition, the new burden for final rule is 91,960 hrs./yr. (hospital and
laboratory must check each batch, lot hospital and independent laboratories is independent laboratories) + 164,906
number and shipment of lactophenol 275,880 hrs/yr.—183,920 hrs./yr. = hrs./yr. (total POLs, those operating on
cotton blue for intended reactivity with 91,960 hrs./yr. a 9 or 10 hour day and those operating
control organism(s). Previously, control on an 8 hour day) = 256,866 hrs./yr.
testing of this stain was required daily. Former Burden: POLs
As described above, since the decrease Section 493.1273 Standard:
in this burden for documenting a single For POLs that only perform Histopathology
control result is minor, we are unable to hematology for 8 hours a day, there is The revisions to this requirement
accurately estimate the change. no reduction in burden. However, many result in an increase in reporting from
POLs have operating hours that range one control slide to two control slides
Section 493.1269 Standard: from 9 to 10 hours a day and these for each group of slides for
Hematology laboratories are currently required to immunohistochemical stains.
In the former regulations for the run control materials twice a day. In Previously, we included these reporting
specialty of hematology, under estimating the burden for this category requirements with the general QC
paragraph (b), nonmanual hematology of laboratories, we are including the procedures. The requirements are now
testing systems, excluding coagulation, POLs and the ‘‘other’’ category for a under the condition Analytic systems at
the laboratory was required to include total of 23,557 laboratories. In addition, § 493.1250 as requirements for
two levels of control materials each 8 we estimate that 50 percent (11,779) of Histopathology at § 493.1273. Although
hours of operation. In this final rule, these laboratories operate on a 9 or 10- this is an increase in reporting from one
this requirement has been revised from hour day for 20 days a month and must control slide to two, we cannot estimate
every 8 hours to each day of testing run control materials twice a day. the laboratory burden because we do not
under § 493.1256 and results in Therefore, the burden is 3.5 min./day × know the number of laboratories that
decreased reporting. 20 days/month = 70 min./month = 1.2 perform immunohistochemical stains or
The revisions to this requirement hrs./month × 12 months/yr. = 14 hours/ how often the staining is performed.
result in a decrease in documenting laboratory/yr. × 11,779 laboratories Additionally, many of the laboratories
control results since the requirement (operating on a 9 or 10 hour day) = performing immunohistochemical stains
has been revised from every 8 hours to 164,906 hrs./yr. were already testing both a positive and
each day of testing. The remaining 50 percent of the POLs negative control material, and some
Previously, we had included these that only operate on an 8-hour day have immunohistochemical stains can be
reporting requirements with the general no change in burden that is, 1.75 min./ checked for a negative reaction on the
QC procedures. However, since these day × 20 days/month = 35 min./month same slide that contains positive
requirements are now under the = 0.6 hrs./month 0.6 hrs./month × 12 reactive cells. We expect that this
condition, Analytic systems, at months/yr. = 7 hours/laboratory/yr. revision will only affect a limited
§ 493.1250, we have removed these 11,779 laboratories (operating on an 8- number of laboratories, and the increase
in burden will be small.
hematology requirements from the hour day) × 7 hours/yr. = 82,453 hrs./
general QC procedures and placed them yr. Section 493.1278 Standard:
under Control procedures at § 493.1256. Histocompatibility
Change in Burden: POLs
Former Burden: Hospital and In the former § 493.1265(a)(13), the
Independent Laboratories In this final rule, all laboratories will laboratory was required to have, at least
only be required to run control materials once each month, each individual
The total number of laboratories once each day. Therefore, the POLs performing tests evaluate a previously
performing hematology testing is operating on a 9 or 10-hour schedule tested specimen as an unknown to
32,753. Of this total, 5,329 are hospitals, will have their burden decreased by 50 verify his or her ability to reproduce test
3,867 are independent laboratories, percent. The estimated decrease in results. Records of the results for each
17,844 are physician’s office burden for this group of laboratories individual had to be maintained. These
laboratories (POLs), and 5,713 fall into under this requirement is 11,779 POLs requirements are deleted in this final
a miscellaneous category of others. We (operating on 9 or 10 hour day) × 7 hrs./ rule.
assume that this burden will affect most yr. = 82,453 hrs./yr.
hospitals and independent laboratories Former Burden
since these laboratories typically Former Burden: Total There is a reduction in burden for this
operate 24 hours per day for 30 days a specialty since, in this final rule, we are
month. Therefore, the burden for these The total estimated burden was no longer requiring the laboratories to,
laboratories is 5 min./day × 30 days/ 275,880 hrs./yr. (hospital and at least once each month, have each
month = 150 min./month = 2.5 hrs./ independent laboratories) + 164,906 individual performing tests evaluate a
month 2.5 hrs./month × 12 = 30 hrs./ hrs./yr. (POLs operating on a 9 or 10 previously tested specimen as an
laboratory/yr. 9,196 hospital and hour day) + 82,453 hrs./yr. (POLs unknown to verify his or her ability to
independent laboratories × 30 hrs./yr. = operating on an 8 hour day) = 523,239 reproduce test results. Therefore, we
275,880 hrs./yr. hrs./yr. estimate that the former reporting
Change in Burden: Hospital and Change in Burden: Total burden for this activity to be 3 min./day
Independent Laboratories for each individual, or 3 min./day × 1
The total estimated decrease in month = 3 min./month × 12 months/yr.
Since this final rule will only require burden for this requirement under this = 36 min/yr. = 0.6 hrs/individual/yr.
controls once a day, we are allowing a final rule is 183,920 hrs./yr. (hospital We estimate an average
2⁄3 decrease in burden for these and independent laboratories) + 82,453 histocompatibility laboratory to employ
laboratories. Therefore, the decrease in hrs./yr. (POLs) = 266,373 hrs./yr. three individuals. Therefore, the former
burden is three individuals × 0.6 hrs./ major rules with economically affected. This includes laboratories
yr. = 1.8 hrs/laboratory/yr. significant effects ($100 million or more performing unmodified moderate
There are 264 laboratories performing in any 1 year). This regulation has no complexity testing approved or cleared
histocompatibility testing; therefore, the budget implications that impact by the FDA, and laboratories testing in
estimated burden for this requirement in Medicare benefit payments. We have, microbiology, syphilis serology,
this final rule is 264 histocompatibility however, performed a complete immunology, and hematology. Although
laboratories × 1.8 hrs./yr. = 475 hrs./yr. regulatory impact analysis, although the we had insufficient data and
specified thresholds to require a full information to calculate some of the
Change in Burden analysis may not have been met. costs and savings that may result from
Since this burden is not required in The RFA requires agencies to analyze these changes, we estimate the overall
this final rule, we estimate the decrease options for regulatory relief of small impact will result in a savings of
in burden to be 475 hrs./yr. businesses. For purposes of the RFA, approximately $23 to $38 million the
small entities include small businesses, first year and $101 to $166 million over
Section 493.1291 Test Report nonprofit organizations, and the next 5 years (Tables 1 and 2). The
The following information collection government agencies. Most hospitals term ‘‘savings’’ as used in this RIA is
requirements under paragraph (c) are and most other providers and suppliers defined as reduced compliance costs for
new: The test report must indicate (1) are small entities, either by nonprofit laboratories subject to the CLIA
either the patient’s name and status or by having revenues of $11.5 regulations.
identification number or a unique million or less in any 1 year. For The most significant change in this
patient identifier and identification purposes of the RFA, all laboratories are final rule is related to the delayed
number; (2) the test report date; and (3) considered to be small entities. effective dates (phase-in period) that
the specimen source, when appropriate. Individuals and States are not included allowed laboratories performing
While this information collection in the definition of a small entity. unmodified moderate complexity
requirement is subject to the PRA, we In addition, section 1102(b) of the Act testing approved or cleared by the FDA
believe the burden with it is exempt as requires us to prepare a regulatory to meet certain general QC
defined in 5 CFR 1320.3(b)(2) because impact analysis if a rule may have a
requirements. Laboratories performing
the time, effort, and financial resources significant impact on the operations of
this type of testing did not have to verify
necessary to comply with the a substantial number of small rural
methods before their introduction for
requirement are incurred by persons in hospitals. This analysis must conform to
patient testing or to periodically verify
the normal course of their activities. the provisions of section 604 of the
calibration. As shown in Table 1, we
If you comment on these information RFA. For purposes of section 1102(b) of
expect this change to immediately
collection and record keeping the Act, we define a small rural hospital
impact 29,601 Certificate of Compliance
requirements, please mail copies as a hospital that is located outside of
and COLA-accredited laboratories. We
directly to the following: a Metropolitan Statistical Area and has
estimate the cost of completing the QC
Centers for Medicare & Medicaid fewer than 100 beds.
Section 202 of the Unfunded phase-in period to be between $28.3
Services, million and $37.1 million the first year
Office of Strategic Operations and Mandates Reform Act of 1995 also
requires that agencies assess anticipated and between $124.1 and $162.5 million
Regulatory Affairs, ORDI, DRD–B, Attn: over the next 5 years.
Julie Brown, Room N2–14–26, 7500 costs and benefits before issuing any
rule that may result in an expenditure Additional changes in this final rule
Security Boulevard, Baltimore, MD will impact laboratories performing
21244–1850. by State, local, or tribal governments, in
the aggregate, or by the private sector, of various specialties and subspecialties.
Office of Information and Regulatory The impact of these changes will vary
Affairs, Office of Management and $110 million. This final rule does not
mandate any requirements for State, depending on the volume and frequency
Budget, Room 10235, New Executive of testing being done in each specialty
Office Building, Washington, DC 20503, local, or tribal governments, or by the
private sector. Therefore, we certify that or subspecialty.
Attn: Brenda Aguilar, CMS Desk Officer. Overall, the changes in microbiology
this rule would not have a significant
VII. Regulatory Impact Analysis economic impact on a substantial will result in significant savings of
number of small entities or a significant approximately $55.9 million the first
Overall Impact year and $245.2 million over the next 5
impact on the operations of a substantial
We have examined the impacts of this number of small rural hospitals. years. The changes in bacteriology and
rule as required by Executive Order Executive Order 13132 establishes mycology are based on data
12866 (September 1993, Regulatory certain requirements that an agency demonstrating that for several reagents,
Planning and Review), the Regulatory must meet when it promulgates a QC is not required as frequently as
Flexibility Act (RFA) (September 16, proposed rule (and subsequent final required under the previous regulation.
1980, Pub. L. 96–354), section 1102(b) of rule) that imposes substantial direct We assume the changes in bacteriology
the Social Security Act, the Unfunded requirement costs on State and Local will affect 27,443 laboratories and result
Mandates Reform Act of 1995 (Pub. L. governments, preempts State law, or in immediate savings of $62.4 million
104–4), and Executive Order 13132. otherwise has Federalism implications. and aggregate savings of $273.7 million
Executive Order 12866 directs We have determined that this final rule over the next 5 years. In addition, we
agencies to assess all costs and benefits does not significantly affect States’ expect changes in mycology to affect
of available regulatory alternatives and, rights, roles, and responsibilities. 9,059 laboratories with immediate
if regulation is necessary, to select annual savings of $1.4 million and
regulatory approaches that maximize A. Executive Summary approximately $6.1 million savings over
net benefits (including potential This final rule includes changes that the next 5 years. For mycobacteriology,
economic, environmental, public health will impact many laboratories and we are requiring more frequent QC
and safety effects, distributive impacts, indirectly impact manufacturers of test testing and expecting this change to
and equity). A regulatory impact systems and controls. Most laboratories affect 3,185 laboratories with an
analysis (RIA) must be prepared for that perform nonwaived testing will be estimated increase in costs of $7.9
million the first year and $34.6 million with the provisions of the rule disruptive burdens associated with
over the next 5 years. concerning directors who are not board currently employed individuals
Laboratories performing testing in certified until the effective date of this obtaining board certification and
syphilis serology (7,634), immunology new rule, to the extent the facilities are laboratories replacing currently serving
(20,665), and hematology (32,753) can otherwise in compliance with the directors.
perform less frequent QC testing. We are requirements for laboratory directors. In summary, in the first year, we
unable to estimate the savings because This means that on and after February estimate the sum of all costs to be $36.2
we do not know how often the testing 24, 2003, individuals with a doctoral to $45.0 million with savings of $63.8
will be performed. degree who have not been grandfathered
Finally, we are including a number of million and a net saving of $18.8 to
in as directors will need to be board
other changes that we are not $27.6 million the first year. Over the
certified to serve as directors of
considering burdensome. In many cases, next 5 years, we estimate the sum of all
laboratories performing high complexity
we expect these other changes to have costs to be $158.7 to $197.3 million, a
testing. The grandfather provision
positive impacts; however, we are not allows those individuals with a doctoral total saving of $279.8 million, and a net
able to quantify the consequences. degree who have served or are currently saving of $82.5 to $121.0 million.
Among these changes is the completion serving as high complexity laboratory In addition to overall monetary
of the phase-in period for the laboratory directors and have at least 2 years of savings, this analysis acknowledges the
director qualification requirement for training or experience, or both; and 2 potential for improvements in test
high complexity testing that allowed an years of experience directing or accuracy and lower error rates in patient
individual with a doctoral degree and supervising high complexity testing as testing. We expect there to be
the specified training and experience to of December 31, 2002 to continue in this improvements in the accuracy of patient
qualify as a director of a laboratory capacity without obtaining board testing and in accuracy of moderate
performing high complexity testing in certification. In the absence of this complexity testing resulting from
lieu of board certification up until provision, the experienced individuals performance of method verification and
December 31, 2002. To ensure a smooth who have a doctoral degree without calibration verification, and additional
transition to the new provisions for board certification and have served or QC testing in mycobacteriology. We also
directors of high complexity testing who are serving as directors of laboratories expect more timely identification of
are not board certified (but who have performing high complexity testing potential laboratory errors resulting
doctoral degrees), we will not be would be ineligible to continue serving from the grading of more proficiency
holding facilities out of compliance as a director, resulting in costly and testing (PT) challenges.
TABLE 1.—IMPACTS DUE TO REGULATORY CHANGES: FIRST YEAR AND 5 YEAR TOTALS
First year 5 Year total
Labs affected Savings (costs) † Labs affected Savings (costs) †
Method Verification ........................................ 11,248 ($11.3–20.1) ..................... 29,601 ($49.6–88.0)

Calibration Verification ................................... 29,601 (17.0) ................................ 29,601 (74.5)
Microbiology Changes ................................... .............................. ........................................... ..............................
Bacteriology ................................................... 27,443 62.4 ................................... 27,443 273.7
Mycology ........................................................ 9,059 1.4 ..................................... 9,059 6.1
Mycobacteriology ........................................... 3,185 (7.9) .................................. 3,185 (34.6)
Microbiology Total ......................................... .............................. 55.9 ................................... .............................. 245.2
Less QC for Other Specialties ...................... .............................. ........................................... ..............................
Syphilis serology ............................................ 7,634 Unknown savings ............. 7,634 Unknown savings
Immunology ................................................... 20,665 Unknown savings ............. 20,665 Unknown savings
Hematology .................................................... 32,753 Unknown savings ............. 32,753 Unknown savings
Total ........................................................ .............................. 18.8–27.6 .......................... .............................. 82.5–121.0
†In millions of dollars.
TABLE 2.—IMPACTS DUE TO REGULATORY CHANGES: ANNUAL IMPACTS OVER 5 YEARS

Savings (costs)†
Year 1 Year 2 Year 3 Year 4 Year 5 5-Year total
Method Verification ..... ($11.3–20.1) ....... ($10.6–18.8) ....... ($9.9–17.6) ......... ($9.2–16.4) ......... ($8.6–15.3) ......... ($49.6–88.0)
Calibration Verification (17.0) .................. (15.9) .................. (14.8) .................. (13.9) .................. (13.0) .................. (74.5)
Microbiology Changes: ............................ ............................ ............................ ............................ ............................
Bacteriology ......... 62.4 .................... 58.3 .................... 54.5 .................... 50.9 .................... 47.6 .................... 273.7
Mycology .............. 1.4 ...................... 1.3 ...................... 1.2 ...................... 1.1 ...................... 1.1 ...................... 6.1
Mycobacteriology (7.9) .................... (7.4) .................... (6.9) .................... (6.4) .................... (6.0) .................... (34.6)
Microbiology 55.9 .................... 52.2 .................... 48.8 .................... 45.6 .................... 42.7 .................... 245.2
Total.
Less QC for Other

Specialties:
Syphilis serology .. Unknown ............ Unknown ............ Unknown ............ Unknown ............ Unknown ............ Unknown
Immunology .......... Unknown ............ Unknown ............ Unknown ............ Unknown ............ Unknown ............ Unknown
TABLE 2.—IMPACTS DUE TO REGULATORY CHANGES: ANNUAL IMPACTS OVER 5 YEARS—Continued

Savings (costs)†
Year 1 Year 2 Year 3 Year 4 Year 5 5-Year total
Hematology .......... Unknown ............ Unknown ............ Unknown ............ Unknown ............ Unknown ............ Unknown
Total .............. 18.8–27.6 ........... 17.5–25.7 ........... 16.4–24.1 ........... 15.3–22.5 ........... 14.4–21.1 ........... 82.5–121.0
† In
millions of dollars.
Changes discounted at 7 percent compounded annually after Year 1.
B. Introduction As part of the QC phase-in, the FDA Moderate and High Complexity Testing
The changes in this final rule will was to establish a process for review This final rule updates requirements
have some impact upon nearly all and clearance of manufacturers’ test and recognizes the improvements in
laboratories performing nonwaived system instructions for compliance with technology and stability of reagents by
testing. The nature and magnitude of the certain CLIA QC requirements. This reducing the frequency of QC testing in
specific effects on any particular provision would have allowed several specialty and subspecialty areas
laboratory will depend upon the volume laboratories to meet the CLIA QC that include both moderate and high
and types of testing performed and the requirements by following the complexity testing. For the following
QC requirements it met under the manufacturers’ FDA-approved or specialties and subspecialties, we
former regulation. The most significant cleared instructions. However, because reduced the frequency of QC testing,
impact will be on laboratories the CLIA program is user fee funded, we relieving laboratory burden and
performing unmodified moderate decided it would be prudent to wait lowering the cost per test:
complexity testing approved or cleared until the phase-in period ended before • Decreased frequency of QC testing
by the FDA that have been following the implementing the FDA QC review. This for bacteriology and mycology reagent
minimal QC requirements provided afforded us the survey experience checks.
during the QC phase-in period. With the necessary to determine whether an • Decreased frequency of QC testing
completion of the phase-in, these additional FDA review process beyond for general immunology and syphilis
laboratories may now be required to that already in place as part of serology to daily testing from concurrent
follow more stringent QC procedures. premarket review would be of benefit to with patient testing.
laboratories. We realized through our • Decreased frequency for hematology
QC Phase-in Requirements experience inspecting laboratories that QC testing to each day of use from each
Under the February 28, 1992 final rule an additional FDA review would not be 8 hours of operation.
with comment period implementing the of such benefit. Therefore, this For the subspecialty of
Clinical Laboratory Improvement prospective provision was removed in mycobacteriology, we increased the
Amendments of 1988 (CLIA), many this rule. frequency of QC testing for the
laboratories that had never been Moderate Complexity Testing following:
regulated were required for the first time • Added a requirement for testing
to establish and perform minimum QC With implementation of this final negative controls to check stains and
and quality assurance practices. Most rule, laboratories performing reagents.
previously unregulated laboratories unmodified, FDA approved or cleared • Increased frequency for checking
were performing primarily waived or moderate complexity testing must now, fluorochrome and acid fast stains.
moderate complexity testing using as applicable—
unmodified commercial test systems. Laboratory Director
• Augment procedure manual
Acknowledging the burden of coming instructions; We are completing the phase-in
under regulation for the first time, we qualification requirements for high
created a phase-in period that allowed • Monitor laboratory environmental complexity laboratory director that
laboratories performing unmodified conditions that affect reagent storage allows individuals with a doctoral
moderate complexity testing approved and test system operation; degree to qualify based on training and
or cleared by the FDA to perform less • Verify or establish performance experience in lieu of board certification
stringent QC procedures than specifications for newly introduced test until February 24, 2003. With the
laboratories performing modified systems; implementation of this final rule on
moderate complexity or high • Record or document equipment February 24, 2003, board certification
complexity testing. In addition, our maintenance and function checks; will be required. To ensure a smooth
intent was that when the phase-in transition to the new provisions for
• Perform calibration verification;
period was complete, all laboratories directors of high complexity testing who
and
performing nonwaived testing would be are not board certified (but who have
subject to the same QC requirements. • Follow control procedures that doctoral degrees), we will not be
This final rule is ending the phase-in monitor the accuracy and precision of holding facilities out of compliance
period for QC that had been extended to the testing process. with the provisions of the rule
December 31, 2002. The QC These changes will primarily impact concerning directors who are not board
requirements for laboratories performing Certificate of Compliance and COLA- certified until the effective date of this
unmodified moderate complexity accredited laboratories, because these new rule, to the extent the facilities are
testing are now essentially equivalent to laboratories perform the bulk of the otherwise in compliance with the
the requirements for modified moderate commercial, unmodified moderate requirements for laboratory directors.
complexity, and high complexity complexity testing that was subject to This new final rule permits those
testing. the QC phase-in requirements. individuals who qualified under the
phase-in provision and have served or complexity testing cleared by the FDA. In this final rule impact analysis, for
are serving as directors of laboratories Other changes in specialty and each regulatory change, as appropriate,
performing high complexity testing and subspecialty QC requirements affect our discussion is organized under the
have at least 2 years of training or laboratories performing both moderate following topics:
experience, or both, and 2 years of and high complexity testing. The • Rationale.
experience directing or supervising high changes in the high complexity • Methodology.
complexity testing to continue to serve laboratory director requirements • Benefits.
as directors. primarily affect laboratories performing • Costs.
high complexity testing that need to hire • Alternative approaches.
Miscellaneous Changes
a director on or after February 24, 2003. 1. Laboratories Affected by Completion
There are a number of minor, As appropriate for each specific change, of the QC Phase-in Characteristics of
miscellaneous changes. Some, like the in addition to the impacts on Affected Laboratories Laboratory
change in the consensus requirements laboratories, we considered the Demographics
for PT grading from 90 percent to 80 potential impacts on manufacturers of
percent, are the result of comments The total number of certified and
laboratory test systems, controls, and
made to the former regulation. For the exempt laboratories in the United States
calibration materials, and possible
most part, these changes are considered (U.S.) is 174,856 (Table 5). This number
impacts on patients.
to have no significant positive or includes a total of 168,688 CLIA-
For this analysis, CDC used the
negative impact. We consider many of certified laboratories (96 percent),
services of Research Triangle Institute
them to be clarifications of implied consisting of 91,540 laboratories with
(RTI) to assist with data collection and
requirements, or standard laboratory Certificates of Waiver (52 percent),
cost-benefit analyses. RTI used data
practices already in place, such as the 38,304 with Certificates for Provider-
concerning current testing practices to
requirement for laboratories to verify Performed Microscopy (PPM, 22
estimate both immediate consequences
accuracy of analytes, subspecialties and percent), 22,720 with Certificates of
and the impact over the next 5 years. A
specialties assigned a PT score that does Compliance (13 percent), and 16,124
7 percent discount rate was applied for
not reflect the laboratories’ actual test with Certificates of Accreditation (9
projections after the first year,
performance. In many cases, we have percent) (OSCAR, April 2001). In
consistent with OMB recommendations
moved specific sections to make the addition, there are 6,168 laboratories in
(Economic Analysis of Federal
regulation fit within the new regulatory the CLIA-exempt States of New York
Regulations under Executive Order
framework (movement of the specimen and Washington (4 percent).
12866). Both RTI and HHS have sought
This final rule will not affect the 74
through the laboratory) and to make the data from a number of sources,
percent of clinical laboratories holding
requirements easier to read and including scientific articles,
Certificates of Waiver and PPM (129,844
comprehend. While we expect positive Government reports, CMS data, CDC
laboratories). Laboratories with a
benefits from these clarifications, it studies, including data from CDC
Certificate of Waiver are only subject to
would be impossible to quantify these cooperative agreements, industry
limited CLIA requirements, they must
benefits. reports, reports by marketing
only perform waived tests and tests
consultants, interviews with
C. Methodology and Approach cleared by the FDA for home use, follow
manufacturers and laboratorians, and
manufacturer’s instructions for testing,
Basis for Estimates and Reliability of studies by professional groups, like the
and maintain their waived certificates.
Projections American Medical Association.
Laboratories with a Certificate for PPM
These projections are based upon For each specific regulatory change,
procedures must meet applicable
some necessary assumptions concerning we outline the parties these changes
requirements in subparts J and K of this
the current and future status of will affect, methodological approach,
final rule (formerly subparts J, K, and P).
laboratory practices, technological necessary assumptions and limitations
PPM procedures were not under the QC
advances, and the marketplace, making in the reliability of the conclusions, and
phase-in; therefore, PPM procedures
some degree of inaccuracy unavoidable. possible alternatives.
were subject to the more stringent
As each change is considered, the D. Impacts requirements in subpart K of the
assumptions are stated. Due to the This discussion of regulatory impacts February 28, 1992 final rule with
limitations in our data and information, is organized as follows: comment period. However, there are no
we used a range of reasonable • Section 1 contains the QC materials for most PPM procedures.
alternatives to estimate future events demographics of the laboratories that For this analysis, we assume that all
and reflect our degree of uncertainty. the completion of the QC phase-in will Certificate of Compliance laboratories
For much of this analysis, we use well- impact. perform some moderate complexity
defined data from CMS Online Survey • Section 2 has specific provisions testing and that these laboratories have
and Certification Reporting System not required during the phase-in period been meeting only the minimum QC
(OSCAR) (2001) concerning laboratory that certain laboratories will now need requirements for FDA-cleared,
demographics and test volume. When to meet. unmodified moderate complexity test
using less defined data, we made • Section 3 has changes in specialty systems under the requirements of the
projections on the more costly side to and subspecialty QC, including changes QC phase-in period. In addition, we
provide an estimation of maximal in microbiology, immunology, syphilis assume the completion of the QC phase-
impact. serology, and hematology. in would affect all of these laboratories
We estimate the impact of these • Section 4 has the completion of the (22,720 laboratories or 13 percent).
regulatory changes for those entities that phase-in requirements for laboratory Similarly, we assume that the
these changes may affect, and we project directors. completion of the QC phase-in will
the impact over the next 5 years. The • Section 5 contains miscellaneous affect the COLA-accredited laboratories
completion of the QC phase-in period changes, Including the change from 90 because COLA’s requirements are
affects a portion of laboratories percent to 80 percent consensus equivalent to the CLIA QC phase-in
performing unmodified moderate requirements for PT results grading. requirements. Therefore, these changes
will impact COLA laboratories (6,881 laboratories (POLs) (65 percent), and ‘‘Other’’ laboratories generally perform
laboratories, 4 percent) when COLA 4,048 Other (18 percent) laboratories testing at a variety of healthcare sites
revises its requirements to be equivalent (Table 3). Since the majority of COLA including home health testing and
to this final rule. Laboratories accredited laboratories are POLs (95 percent, COLA nursing homes.
by organizations other than COLA estimate), we assume all COLA Although the percentages of
currently have QC requirements that are laboratories are POLs for this analysis. laboratories with each certificate type
more stringent than those under the The estimated total number of POLs that remained relatively stable over the past
CLIA QC phase-in. With the adoption of these QC changes will impact is 21,568, several years, the absolute numbers
the requirements in this final rule, CLIA which comprise the largest portion of show trends toward lower complexity
requirements will more closely resemble the 29,601 laboratories (73 percent) we certificates (waiver and PPM). For
these accrediting organizations’ estimated will be affected by this example, from 1998 to 2001, the number
standards for QC. regulation. However, the affected POLs of laboratories with Certificates of
Therefore, we estimate that these QC constitute only 22 percent of all U.S. Compliance decreased by 20 percent
changes will immediately affect 29,601 POLs and 12 percent of all laboratories (5,604), and an increase occurred for
laboratories (17 percent of the Nation’s in the country. The vast majority (77 both Waiver (+9 percent; 7,628) and
laboratories). These laboratories consist percent) of POLs hold Certificates of PPM (+12 percent; 3,988) laboratories
of those with a Certificate of Waiver or PPM. In addition, changes in (Table 4). We expect this trend to
Compliance (22,720) and COLA- this final rule will not immediately continue in the future because of the
accredited (6,881) laboratories. The affect most U.S. hospital laboratories widening availability of waived tests,
22,720 Certificate of Compliance because they are typically accredited, many of which are considered
laboratories that this QC change may rather than Certificate of Compliance important for on-site testing in POLs.
affect consist of 1,392 Hospital (6 laboratories. The additional laboratory Therefore, the long-term impact of this
percent of laboratories with a Certificate types in the CMS OSCAR (2001) regulation may be mitigated by this
of Compliance), 2,593 Independent (11 database classified as ‘‘Independent,’’ continuing decrease in the number of
percent), 14,687 physician office are typically referral testing sites, and Certificate of Compliance laboratories.
TABLE 3.—CERTIFICATE TYPE BY LABORATORY TYPE

Certificate type 1
Compliance Waiver Accreditation PPM State

Laboratory type 5 All
exempt 4
N2 %3 N % N % N % N % N
Hospital .................................................. 1,392 15 1,231 14 5,475 62 224 3 498 6 8,820

Independent ........................................... 2,593 51 910 18 937 18 131 3 515 10 5,086
Physician Office ..................................... 14,687 15 42,927 44 6,416 7 31,510 33 1,391 1 96,931
Other ...................................................... 4,048 7 46,472 76 3,296 5 6,439 10 3,764 2 64,019
All ........................................................... 22,720 13 91,540 53 16,124 10 38,304 22 6,168 2 174,856
1 OSCAR, 2001.
2 Number of Laboratories.
3 Column Percent.
4 Data from NY and WA States.
5 Self Reported.
TABLE 4.—CHANGES IN CERTIFICATE TYPE, 1998 TO 2001

1998 1999 2000 2001
Certificate type 1
N2 %3 N % N % N %
Compliance .............................................................................................. 28,324 17 27,819 16 25,145 15 22,720 13

Waiver ...................................................................................................... 83,912 52 87,754 52 89,998 52 91,540 54
Accreditation ............................................................................................ 16,469 10 17,337 10 15,885 9 16,124 10
PPM ......................................................................................................... 34,316 21 36,789 22 37,535 22 38,304 22
All ............................................................................................................. 163,021 100 169,700 100 171,736 100 171,010 100
1OSCAR, 2001.
2Number of Laboratories.
3Column Percent.
Specific Impact Dependent on Test billion tests for 1996 by Hoerger, percent) Certificate of Compliance
Volume and Laboratory Type Eggleston, Lindrooth and Basker (1997) laboratories perform less than 10,000
and the estimate of 5.7 billion tests for tests per year, with 42 percent
Certificate of Compliance laboratories the year 2000 in an Institute of Medicine performing less than 2,000. For COLA
comprise 13 percent of U.S. laboratories report (Institute of Medicine, 2000). The laboratories, the average annual test
and perform 991 million (19 percent) of average annual test volume per volume is approximately 5,000 tests per
the 5.3 billion tests annually in the U.S.
Certificate of Compliance laboratory is laboratory (COLA, personal
(OSCAR, 2001). Our estimate of 5.3
43,618; however, the test volume communication, June 2001), making the
billion tests for the year 2001 is
distribution is skewed. Most (69 aggregate annual test volume for all
consistent with the estimate of 5.9
COLA laboratories 34 million tests. proportionate costs of testing are greater laboratories had the highest use (83
Among the Certificate of Compliance in low volume laboratories percent) (Steindel, Rauch, Simon, and
laboratories, POLs and laboratories (Tershakovec, Brannon, Bennett, and Handsfield, 2000). This survey was an
under the classification as ‘‘Other’’ tend Shannon, 1995) because of the overhead unbiased on-site inventory of test
to have low annual test volumes, while cost, including those related to CLIA. systems and sampling was weighted to
Hospital and Independent laboratories Another major determinate of the reflect the composition of U.S.
have higher test volumes (Table 5). impact of this final rule that correlates laboratories.
This final rule will affect some aspect with test volume is the extent of We also anticipate that among
of these laboratories differently quantitative testing performed using Certificate of Compliance POLs, the
depending upon their annual test moderate complexity instrumentation. practice size will affect the magnitude of
volume and the number of different test A CDC survey of laboratories found, for the impact. Studies also show that
procedures they perform. Generally, example, that among Certificate of practice size correlates directly with the
laboratories performing a limited Compliance laboratories, the use of extent of on-site testing (Ambulatory
number of different tests will be quantitative testing instrumentation was Sentinel Practitioner Network, 1996).
impacted less than laboratories extremely variable. Use of hematology Therefore, we expect the aggregate
performing a greater number of tests. analyzers varied from a low of 36 impact of this final rule to be less among
The low volume laboratories, POLs and percent among Independent laboratories solo practices since they perform less
Others, will be less impacted because to a high of 77 percent among Hospital testing. However, solo practices have
they tend to have more limited test laboratories; for chemistry analyzers, the fewer employees and financial resources
menus than those in Hospitals and lowest frequency (20 percent) was to execute aspects of this final rule,
Independent laboratories. However, the among POLs, while Hospital which may increase burden.
TABLE 5.—ANNUAL TEST VOLUMES BY LABORATORY TYPE, CERTIFICATE OF COMPLIANCE LABORATORIES ONLY, OSCAR,
APRIL 2001
Number and percent of laboratories grouped by annual test volume
Average
Total
Labora- number Total number 10,000–25,000 tests/
tory number of tests ≤2,00 tests/yr 2,000–10,000 tests/yr >25,000 tests/yr
of labora- yr
type 1 tories of tests 2 per lab-
oratory N3 %4 N % N % N %
Hospital 1,392 354 254,310 444 32 56 4 148 11 744 53

Indepen-
dent ... 2,593 307 118,396 572 22 481 18 433 17 1,107 43
Physicia-
n Of-
fice .... 14,687 147 10,008 6,899 47 4,681 32 1,617 11 1,490 10
Other .... 4,048 183 45,207 1,614 40 968 24 578 14 888 22
All .. 22,720 991 43,618 9,529 42 6,186 27 2,776 12 4,229 19
1 Self-reported.
2 In millions.
3 Number of laboratories.
4 Column percent.
2. Specific Changes Associated with laboratories will require changes to their extent to which they may need to create
Completion of the QC Phase-in Period procedure manual. procedural elements and the number of
In addition, laboratories must now procedures performed in each
a. Procedure Manuals document the dates of initial use and laboratory. The cost for each laboratory
Rationale discontinuance for each procedure; and will be the cost of the labor to augment
all procedures and procedural changes documentation and the laboratory
During the QC phase-in period, must be approved, signed, and dated by director’s time in reviewing, signing,
laboratories performing commercial, the current laboratory director before and dating procedures. We estimate that
unmodified moderate complexity use. these costs will be minimal since most
testing must ‘‘have a procedure manual
Benefits Certificate of Compliance and COLA
describing the processes for testing and
laboratories do not perform a large
reporting patient test results.’’ With the A comprehensive and up-to-date
completion of the phase-in, laboratories number of test procedures and many
procedure manual is essential to ensure
performing this type of testing will now may already have the documentation.
reliable and reproducible performance
be subject to more specific, among individuals and is considered We are unable to estimate the total cost
comprehensive procedure manual one hallmark of good laboratory practice for this requirement since we have no
requirements. Some laboratories may and a necessary component of quality estimate on the extent to which
need to augment their current procedure management. procedure documentation will be
manuals to meet the new requirements. necessary.
Although we are unable to estimate the Costs
number of laboratories and the specific For those Certificate of Compliance
procedure manual changes they will and COLA laboratories that need to
need to make, we estimate that all amend procedure manual instructions,
Certificate of Compliance and COLA the cost will vary depending on the
b. Test Systems, Equipment, the manufacturer’s specifications. asked how many nonwaived new tests
Instruments, Reagents, Materials, and During the QC phase-in period, they added to their test menus between
Supplies laboratories could introduce testing April 1997 and April 1999. Although
using commercial, unmodified moderate these percentages are for a 2-year time
Rationale
complexity test systems approved or period, we conservatively assumed that
With the completion of the QC phase- cleared by the FDA without verifying all tests were adopted during the last
in, laboratories performing commercial, manufacturer’s performance year of the period. We assumed that the
unmodified moderate complexity specifications (accuracy, precision, and incidence of test introduction is roughly
testing must now meet the provisions at reportable range of patient test results) the same for the affected laboratories as
§ 493.1252 for test systems, equipment, before testing patient’s specimens. On for the Sentinel Monitoring Network.
instruments, reagents, materials, and April 24, 2003, all laboratories must Multiplying these percentages by the
supplies. During the phase-in, these perform method verification when total number of laboratories (29,601), we
laboratories were required to ‘‘follow instituting any new moderate calculated the number of laboratories
the manufacturer’s instructions for complexity test and before testing that are expected to add at least one test
instrument or test system operation and patient specimens, as specified in to their test menus in a year,
test performance,’’ which would include § 493.1253. approximately 11,248 (38 percent)
most of the requirements listed in (Table 6).
§ 493.1252. However, now laboratories Methodology
must monitor and document conditions To determine the possible impact, we Estimate of Analyzer Replacement
essential for ‘‘proper storage of reagents did an estimate of the cost of assays to Because of the small sample size, we
and specimens, accurate and reliable verify manufacturers’ performance were not confident that the survey of
test system operation and test result claims for commercial, unmodified laboratories in the Pacific Northwest
reporting.’’ These conditions include moderate complexity tests expected to Laboratory Medicine Sentinel
‘‘water quality, temperature, humidity, be introduced annually among the Monitoring Network accounted for the
and protection of equipment and affected laboratories. For this analysis, replacement of existing multiple analyte
instruments from electrical we assumed that existing moderate analyzers. Replacement of an obsolete
interruptions and fluctuations that complexity test systems would be analyzer with a new model requires
adversely affect patient test results and retired and replaced with a new test verification for each analyte. Therefore,
test reports.’’ system approximately every 5 years the cost of replacing analyzers depends
according to data available for a small upon the existing number of analyzers,
Benefits
population of laboratories. In addition, the number of years of operation before
Monitoring and documenting for cost calculations, we estimated the replacement, the number of tests each
environmental and other conditions number of verification data points analyzer performs, and the labor and
necessary for proper reagent and needed and the costs in terms of labor, reagent cost per assay for method
specimen storage and test performance materials, and reagents to perform these verification. We assumed laboratories
is essential to ensure quality test results. studies. replace analyzers every 5 years and,
When conditions are outside of the The cost of method verification is therefore, compute the number of
prescribed acceptable range, corrective typically greater for quantitative tests analyzers of each type that would
action can be taken. Without monitoring than qualitative tests. In most cases, require replacement each year by
and documentation, laboratories may fewer specimens and less labor and dividing the number of analyzers by
not be aware of conditions that may reagents are required to verify the five.
adversely affect patient test results. performance of qualitative tests. We do NICLTS data (Steindel, et al 2000)
Costs not know the fraction of new tests that gave us the percentage of Certificate of
are qualitative, so we treated all tests as Compliance POL, Hospital, Independent
The costs to implement this if they are quantitative to calculate the and Other laboratories having
requirement will be minimal and will maximal impact. Also, we assumed that chemistry, hematology, therapeutic
include labor to develop and maintain the laboratories that this change will drug, ligand, reproductive hormone, and
a monitoring and documentation affect have not been performing method immunology analyzers. To determine
system. We do not know the extent to verification. However, we know that the total number of each kind of
which the specific commercial, some manufacturers currently offer on- analyzer to be replaced over the next 5
moderate complexity procedures used site verification assistance, and we years, we multiplied these percentages
in each laboratory will require expect that practice to continue; by the number of Certificate of
monitoring of each of these conditions therefore, we may be overestimating the Compliance and COLA laboratories of
or the extent to which laboratories are impact. each laboratory type to obtain the
already performing monitoring and number of laboratories having each kind
documentation of these conditions. Estimates of the Incidence of New Test
of analyzer, and then totaled the
Therefore, we are unable to estimate a Introduction
analyzers in each laboratory type (Table
total cost for this requirement. Data describing how frequently new 7).
c. Method Verification tests or test systems are introduced into
laboratories were limited. For one Benefits
Rationale estimate, we used the percentages of To ensure accuracy and precision, it
Method verification is performed laboratories expected to add zero, one, is especially important to demonstrate
when a new test is brought into the two, three, four, or five moderate acceptable performance for a new test
laboratory and before beginning patient complexity tests to their test menus method before testing patient
testing and result reporting. It consists from a survey of laboratories specimens. Comparing results of the
of studies to verify that the laboratory participating in the Pacific Northwest new method with the manufacturer’s
can obtain accuracy, precision, Laboratory Medicine Sentinel claims and the current method, if the
reportable range and reference intervals Monitoring Network (LaBeau, Simon, method is being replaced, can detect
with the new test system comparable to and Steindel, 1999). Laboratories were biases and problems with
reproducibility and linearity. Also, an together using the same specimens. director time at a rate of $33.45 per hour
evaluation of the appropriateness of the Therefore, our estimate using the (Bureau of Labor Statistics Occupational
reference interval ensures that the test NCCLS protocol, in which we assumed Outlook Handbook, 2000–2001 edition).
can differentiate a normal result from a range of 120 to 150 assays per analyte
Materials
one suggesting a disease process. It is or test, may overestimate the number of
difficult to estimate the number of assays required. For the NCCLS approach, patient
mistakes that can be averted by method materials would suffice; however, these
Reagent Costs must be tested on a separate analyzer
verification. However, it is considered a
hallmark of good laboratory practice to We estimated the cost for reagents by that serves as a reference for accuracy
prevent errors when introducing a new obtaining price quotes from reagent determinations. In addition, we are
test system, by verifying acceptable manufacturers (Beckman-Coulter, Dade- assuming that previously tested, stored
performance of the new methodology Behring and Roche Diagnostics). patient samples would be used;
before testing patient specimens. Because the price estimates vary with therefore, we included locating
test volumes, we assumed a moderate previously tested patient materials in
Costs test volume with an average cost across labor costs.
Number of Tests Needed To Verify analyzers to estimate an average reagent
Total Costs
Method Performance Specifications (Per cost. We also estimated an average
Analyte) reagent cost to be $1.79 per test. We did Based on the incidence of
not include costs for calibration or QC introduction of individual tests reported
There are no standards of practice materials. However, many in the Pacific Northwest Laboratory
established for method verification, and manufacturers provide assistance to Medicine Sentinel Monitoring Network
there is great variability in what laboratories for method verification, and survey (LaBeau, et al 1999), the cost of
laboratories currently do to verify this assistance many times includes the requirement to perform method
performance specifications. The NCCLS providing reagents to the laboratory free verification among affected laboratories
has published several guidelines for of charge. Although manufacturers will can range from $8.3 to $15.3 million the
verification of the elements of incur some cost for reagents, the cost is first year (Table 6). Considering the
acceptable performance. One way to significantly less than the retail sales costs of method verification for
document performance is to use NCCLS price we quote. replacement analyzers, the costs can
protocols, document EP15–P for range between $3.0 and $4.8 million
accuracy and precision, EP6–P for Labor Estimates (Table 7). Therefore, the total first year
linearity (reportable range), and C28–A Because we do not know the average expense for method verification may
for reference intervals. The three number of analytes per test system, we range from $11.3 to $20.1 million. The
separate protocols require a total of 120 assumed a broad range of analyst time aggregate impact for method
assays, at a minimum. Reducing this (4 to 16 hours) at a rate of $17.90 per verification, with a discount over the
number can be accomplished by hour (Ward-Cook and Tannar, 2001). We next 5 years, may range from $49.6 to
performing some of the analyses are also assuming 1 hour of laboratory $88.0 million.
TABLE 6.—IMPACT OF METHOD VERIFICATION, NEW SINGLE TESTS

Number Number Lab direc- Total cost
Percent of labora- Med tech labor Total labor Reagent cost
Number of tests of tests tor labor methods
adding tories cost (range) * cost (range)* (range)*
added cost* (range)
adding
0 ....................................... 62 18,353 0 0 0 0 0 0
1 ....................................... 16 4,736 4,736 $0.34–1.36 $0.16 $0.50–$1.52 $1.02–1.27 $1.51–2.79
2 ....................................... 8 2,368 4,736 0.34–1.36 0.16 0.50–1.52 1.02–1.27 1.51–2.79
3 ....................................... 5 1,480 4,440 0.32–1.27 0.15 0.47–1.42 0.95–1.19 1.42–2.61
4 ....................................... 4 1,184 4,736 0.34–1.36 0.16 0.50–1.52 1.02–1.27 1.51–2.79
5 ....................................... 5 1,480 7,400 0.53–2.12 0.25 0.78–2.37 1.59–1.99 2.37–4.38
...................................... ................ ................ 26,048 1.87–7.47 0.88 2.75–8.35 5.60–6.99 8.32–15.33
* Millions of dollars
TABLE 7.—IMPACT OF METHOD VERIFICATION, ANALYZER REPLACEMENT

Number of Medical tech- Laboratory
Number of analyzers Total replacement
Analyzer type nologist labor director Total labor cost* Reagent cost *
analyzers replaced cost *
cost* labor cost*
each year
TDM ................. 3,230 646 $46.3–185.0 $21.6 $67.9–206.6 $0.45–0.56 $0.51–0.76

Chemistry ......... 7,657 1,531 109.6–438.6 51.2 160.9–489.8 1.10–1.38 1.26–1.87
Hematology ...... 12,439 2,488 178.1–712.5 83.2 261.3–795.7 0.27–0.34 0.53–1.13
Ligands ............. 3,404 681 48.7–195.0 22.8 71.5–217.7 0.25–0.33 0.32–0.52
Reproduction .... 930 186 13.3–53.3 6.2 19.5–59.5 0.27–0.33 0.29–0.39
Immunology ...... 223 45 3.2–12.8 1.5 4.7–14.3 0.06–0.08 0.07–0.09
...................... .................... .................... 399.3–1,597.1 $186.5 585.8–1,783.7 2.18–2.72 2.98–4.77
TDM = Therapeutic drug Monitoring.
* Thousands of dollars.
* Millions of dollars.
Assumes tests per analyzer: TDM = 2, the FDA performed testing without those laboratories that these changes
Chemistry = 15, Hematology = 1, meeting the calibration verification will affect.
Ligands, Reproduction & Immunology = requirement. On April 24, 2003, the In order to estimate the number of
5 phase-in period ends, and all analytes per laboratory, we analyzed
Assumes reagent cost per test: TDM = laboratories must perform calibration data from three proficiency testing
$2.88, Chemistry = $0.40, Hematology = verification at least every 6 months for programs that target POLs (Medical
$0.90, Ligands = $3.00, Reproduction = each quantitative nonwaived test, as Laboratory Evaluation, American
$2.38, Immunology = $2.38 appropriate. Calibration verification is Proficiency Institute, and College of
done to ensure that the test results are American Pathologists’ Excel) as a gauge
Reliability of Estimates of the numbers of tests offered among
accurate throughout the reportable range
The impact of method verification on of patient results for each test system. those laboratories these changes will
any particular laboratory will depend on affect. From these data, we estimated
how many tests are introduced in any Methodology average test menus of fifteen chemistry
given year. The impact will be more on To determine the impact, we analytes, two therapeutic drugs, one
laboratories that are frequently estimated the number of laboratories hematology analyte, and five for each
expanding test menus, replacing test these changes will affect, their current ligand, immunology, and reproductive
methods or test systems rather than menus of quantitative tests for which testing analyzer. Using this model, the
those maintaining test menus and test calibration verification would be specific number of analytes that must be
systems. Obviously, any start-up applicable, the number of data points verified has little impact on the
laboratory performing nonwaived needed for verification and the costs in estimates because most of the expense is
testing would be verifying the entire test terms of labor, verification materials and in the verification kits.
menu. Nearly two-thirds of the reagents. Number of Data Points To Verify
laboratories in the Pacific Northwest Calibration
Sentinel Network introduced no test Number of Laboratories This Change
systems during the 2-year interval and Will Impact At a minimum, laboratories must
none introduced more than five check three points in the reportable
We assumed that this QC change will
(LaBeau, et al, 1999). Therefore, we range to verify calibration, that is, the
affect all 29,601 laboratories, since
believe while our estimates may low, mid, and high points of the range.
Certificate of Compliance and COLA
accurately describe the impact on the Although there is no requirement to
laboratories perform some moderate
universe of affected laboratories, for any perform duplicate testing at each level,
complexity testing. In addition, we
particular laboratory, we may have it adds information about precision
assumed these laboratories have not
underestimated or overestimated the while adding very little to the cost of the
been performing calibration verification
consequences. procedure. Therefore, we included
on commercial, unmodified moderate
Discussions with manufacturers duplicate testing. We estimated that six
complexity test systems.
revealed that assistance with method data points are the minimum for
verification is often included in the cost Laboratory Menus of Tests With adequate calibration verification, three
of buying or leasing an instrument or Verifiable Calibration concentrations in duplicate. Since
other new test system, regardless of the calibration verification must be
Calibration verification is performed performed at least twice yearly,
size of the laboratory. Regardless of for quantitative testing. For this
whether the manufacturer assists in the laboratories must collect a total of at
analysis, we focused on multi-test least twelve data points for each analyte
verification process, the laboratory or clinical analyzers for which calibration
the manufacturer or both will incur every year.
verification materials are commercially
costs. What is relevant to the impact is available. Specifically, we estimated the Benefits
whether the frequency of the method fraction of laboratories that have
verification will change. Since method We believe that calibration
analyzers for performing quantitative verification can reduce errors in patient
verification already frequently occurs in tests for chemistry, therapeutic drug
the absence of regulation and testing by periodically providing
monitoring, ligands, reproductive information on the accuracy of an assay
manufacturers often provide assistance, hormone testing, hematology, and
our estimate of the total cost of method after it is calibrated, after any major
immunology. By ‘‘ligands’’ we mean maintenance or after problems are
verification probably overstates the analytes measured by immunoassay, for
incremental impact of the new detected in routine QC. However, we are
example carcinoembryonic antigen, not aware of any studies demonstrating
requirement. However, we were unable cortisol, and folate.
to quantify how frequently method the affect of calibration verification on
verification is performed currently, Number of Analytes Per Analyzer error rates.
thereby preventing us from precisely For the purposes of estimating reagent Labor Costs
estimating the incremental change in consumption, we estimated the number For estimates of labor costs, we
the frequency of method verification of analytes being done by multi-test assumed that 2 hours per year will be
when this regulation becomes effective. analyzers. We assumed that the sufficient for each analyte for both
Therefore, we may have overstated or variability of laboratory types and sizes performing the assay and inspecting the
understated the number of assays that would affect the number of different results for acceptable performance. This
laboratories will actually do to verify tests being performed; however, we estimate may be too low in some
performance. were unable to account for the instances and too high in others. The
d. Calibration Verification variability in this model. Because POLs cost of the analyst time, $17.90 per
comprise the largest portion of the hour, is the 2000 mean wage per hour
Rationale laboratories that these changes will for a staff medical technologist from
During the phase-in period, affect and POLs tend to have relatively Ward-Cook and Tannar (2001). In
laboratories performing unmodified limited test menus, we assumed most addition, we assumed that the labor cost
moderate complexity testing cleared by laboratory menus to be minimal among of calibration verification per year is the
time we estimated it takes to perform tests that may not be offered on a multi- assumed to be, at a minimum,
the calibration verification (2 hours), test analyzer. biannually.
multiplied by the analyst wage per hour Our evaluation shows the costs were Scope of Impact
($17.90). roughly similar for the various
Based upon these assumptions and
Cost of Verification Materials calibration verification products. The
estimates, we calculated the total cost of
cost of calibration verification kits was
the requirement to perform calibration
Materials used for calibration obtained from several different
verification for laboratories that these
verification span the reportable range of suppliers of calibration verification
changes will affect to be $17.0 million
the method, and target values are materials (College of American
the first year, and the discounted cost
assigned independently using accurate Pathologists, CASCO NERL Diagnostics,
will be $74.5 million by the end of the
test methods. Acceptable materials are Align, Sigma, R&D Systems, and Streck
next 5 years (Table 8).
proficiency testing material, altered and Laboratories). The average cost for a
The impact to an individual
unaltered previously tested patient year’s worth of calibration verification
laboratory will be proportional to the
specimens, primary standards or materials for comparable products was
number of quantitative tests that need
reference materials, independent used as the cost of verification materials calibration verification. Larger
calibrators, or materials for for each analyzer type . laboratories with more analyzers and
demonstrating linearity or calibration methods will need to perform
Reagent Costs
verification kits. For this analysis, we calibration verification on more
assumed laboratories will purchase We estimated the cost of reagents methods than smaller laboratories with
calibration verification kits. However, from price quotes by analyzer fewer methods. Larger laboratories may
all materials mentioned above may be manufacturers (Beckman-Coulter, Dade- also have more instrument repairs and
used as long as the entire reportable Behring, and Roche Diagnostics). This reagent changes that may make it
range is tested with at least three cost varies with test volume. We used necessary to perform calibration
concentrations and the nominal the moderate volume estimate provided verification more than twice a year.
concentrations are independently by these manufacturers for each Therefore, large laboratories are more
assigned with a valid test methodology. analyzer type, since most of the likely to incur a greater increase in the
Also, we assumed that a laboratory with laboratories that these changes will cost of calibration verification than
any multi-test analyzer would buy a affect perform low to moderate test small laboratories.
product to verify calibration of all tests volumes. We calculated the total cost of In addition, some manufacturers may
the analyzer is capable of performing. reagents by multiplying the cost of furnish calibration verification materials
We may be overestimating the cost reagents per test times the number of and assist in the performance of
because some laboratories do not analytes per analyzer, the minimum calibration verification as part of their
perform all tests available on an number of tests per calibration service. We cannot estimate the extent
analyzer, or we may be underestimating verification, and the frequency of that this may happen; therefore, we may
the cost by not including individual calibration verification, which we have overestimated the total cost.
TABLE 8.—IMPACT OF REQUIREMENT FOR CALIBRATION VERIFICATION

Laboratories Cost of Cost of re- Total costs
affected for Labor costs verification Total costs
Test category agents per per labora-
each test per year materials per year †
year tory
category per year
Ther. Drug Monitoring * .................................................... 3,230 $35.80 $413.00 $69.12 $517.77 $1.67
Chemistry ......................................................................... 7,657 35.80 707.00 72.00 815.05 6.24
Hematology ...................................................................... 12,439 35.80 575.00 10.80 621.60 7.73
Ligands ............................................................................. 3,404 35.80 207.00 36.00 278.80 0.95
Reproductive .................................................................... 930 35.80 158.00 142.80 336.15 0.31
Immunology ...................................................................... 223 35.80 150.00 142.80 328.10 0.07
Total .......................................................................... .................... .................... .................... .................... .................... 16.98

* Therapeutic drug monitoring.
† Cost in millions.
e. Documentation of Maintenance and perform them. With the completion of provides a record for the laboratory to
Function Checks the phase-in, these laboratories must attest maintenance was performed
perform the maintenance and function according to the required schedule and
Rationale
checks according to the manufacturer, to ensure that instrument function is
During the QC phase-in period, but also document their performance within acceptable limits whenever
laboratories performing commercial, and results, as appropriate, and ensure patient testing is performed. This
unmodified moderate complexity that function checks are within the documentation is an essential element
testing were required to ‘‘follow manufacturer’s established limits before of good laboratory practice and
manufacturer’s instructions for patient testing is conducted as specified laboratory quality management.
instrument or test system operation and in § 493.1254.
Costs
test performance.’’ Therefore, if the Benefits
manufacturer had specific instrument For those laboratories that have not
maintenance procedures or function Documentation of routine instrument been documenting maintenance and
checks, the laboratories were required to maintenance and function checks function checks, the cost to initiate this
process will depend on the labor needed for FDA-cleared, unmodified moderate quantitative testing. Laboratories
to develop a documentation system. complexity testing during the phase-in affected by the completion of the QC
Subsequent costs will be for the labor period. This includes testing controls in phase-in might incur costs to establish
necessary to maintain documentation, the same manner as patient specimens, this practice, since this is a new
the number of instruments involved and rotating control testing among all requirement. This verification is simply
the extent to which documentation is operators who perform specific tests, done through repetitive testing to ensure
not currently being done. We have no and verifying the criteria for control that the laboratory’s results are within
data to estimate the total cost to fulfill results acceptability for quantitative the control manufacturer’s statistical
this requirement; however, it will be of tests. parameters for the particular test system
minimal impact. Benefits in use. We have no data on the current
f. Control Procedures prevalence of this activity for those
The requirements for control
laboratories that this change may affect.
Rationale procedures between those in effect
For laboratories that have not been
during the phase-in and this final rule
The intent of the CLIA regulation was are similar. While enforcement was performing this verification, the costs
to impose the same requirements on all permissive during the phase-in, there they will incur will be for the reagents
U.S. laboratories, regardless of testing were no specific guidelines for and controls for replicate testing and for
site, in order to assure the public that laboratories to follow. With this final the labor in testing and evaluating the
minimum standards for quality testing rule, laboratories will have guidance on statistical parameters. In many cases,
were met wherever testing was what control procedures are acceptable replicate control testing can be done
performed. Under the QC phase-in (criteria will be specified in the SOM). concurrent with patient testing, if the
requirements, laboratories performing In addition, the regulatory language is control results are within the
testing using unmodified moderate more specific, providing laboratories manufacturer’s stated range, reducing
complexity test systems approved or more detailed descriptions of what is the cost of this requirement.
cleared by the FDA were required to test required. Also, with the recognition that Laboratories not performing this
two levels of control materials each day technology has and continues to verification will use controls at an
of testing. Since many laboratories had improve, manufacturers will have more increased rate; however, they may offset
never been regulated, they were given a incentive to continue simplifying and this cost by the ability to use more
phase-in period to allow them to improving technology to further reduce internal or procedural QC. We have
become accustomed to meeting the cost of QC. insufficient data to estimate the total
requirements for QC. During the phase- costs for this requirement.
in, laboratories, could through the Costs
guidance in Appendix C of the State Most information on the prevalence of Alternative Approaches
Operations Manual (SOM), use test the reliance on internal checks and
In revising these regulations, we
system internal checks and controls, for controls in lieu of using traditional
external controls is anecdotal (American considered maintaining the QC phase-in
example, built in procedural or
Association for Clinical Chemistry, requirements for QC. These phase-in
electronic checks, as a substitute for one
1999). A study by the Pacific Northwest requirements were intended to
or both levels of traditional external
Laboratory Medicine Sentinel temporarily exempt most previously
liquid controls.
With the completion of the QC phase- Monitoring Network (LaBeau, et al, unregulated laboratories from the more
in, all laboratories performing 1999), demonstrates that the majority of stringent QC requirements such as
nonwaived testing are subject to the the 83 laboratories completing the calibration verification and method
requirements specified in § 493.1256 for survey used mechanisms other than verification. Previously unregulated
control procedures. The minimal daily testing of traditional external laboratories have had sufficient time to
number of control materials and liquid controls for a total of 184 become familiar with regulatory
frequency for control testing remains nonwaived tests. These control requirements. Although few studies
unchanged, two levels of control mechanisms included built-in controls, have been done linking the performance
materials at least once each day of procedural controls, electronic control of QC procedures with patient results
testing. We will continue to allow cartridges or devices, and control strips. (Astles, et al, 1998), the standards
flexibility for laboratories to follow Although external controls were used specified in this final rule are generally
control procedures determined to be with 85 percent of these tests, the considered to be basic quality
equivalent to testing two levels of frequency varied. Only 15 percent used requirements. Also, to maintain the
external controls each day of testing. external controls daily, while the phase-in requirements would create a
We are acknowledging that laboratory majority of the laboratories (64 percent) permanent inappropriate discrepancy
technology has become simpler since used external controls with each kit or between what is required among the
the initial CLIA regulations were lot of reagents. However, this study laboratories having different types of
promulgated, and simplification and sample size is too small to draw general certificates and between moderate and
improvements are continuing. These conclusions about the use of control high complexity testing. Accredited
technological advances may allow for procedures in most laboratories. Since laboratories, with the exception of those
control procedures equivalent to the we anticipate maintaining the status quo accredited by COLA, and State-exempt
traditional daily evaluation of two levels allowing the use of internal checks and laboratories are already required to meet
of external control materials, for internal controls, and the testing of more stringent QC practices than those
example, the use of internal checks and external control materials at the allowed during the phase-in. We believe
internal controls or performance of frequency currently being performed in the completion of the QC phase-in
control procedures at a frequency other most laboratories for unmodified requirements is in the best interest of
than daily. moderate complexity testing, there will the public to ensure the minimum
Additionally, laboratories must now be no impact on the cost. quality laboratory standards regardless
meet some requirements for control use All laboratories must now verify of testing site and the type of testing
and acceptability that were not included control results acceptability for performed.
3. Changes in Specialty and each reagent was less than 2 percent, mycobacteria requiring additional
Subspecialty QC Requirements except for X factor strips/disks, which testing for accurate identification is
a. Changes to Specific Microbiology QC was 2.13 percent. The results of this increasing significantly. To some extent,
Rationale study prompted the ASM to propose false positive results leading to
that reagent QC be required only with inaccurate diagnoses and unnecessary
We are changing the requirements for each new lot for commercial or inappropriate therapy could be
some specific QC practices in microbiology reagents having a 98 reduced by including a negative reagent
microbiology in response to public percent or greater success rate. On the control with biochemical identification
comments, including recommendations basis of these study results and ASM’s tests. Therefore, in this regulation,
made by the American Society for recommendations, in this regulation, we
Microbiology (ASM). The changes affect negative controls are now required in
are lowering the required frequency for
the subspecialties of microbiology, addition to positive controls each day of
reagent QC for several bacteriology tests
including bacteriology, and two mycology tests (Table 9). use for mycobacteriology reagents. In
mycobacteriology, and mycology. For mycobacteriology, we are addition, positive and negative controls
In 1996, the ASM (ASM, 1996) increasing some QC requirements based are now required each day of use for
reported to the CLIAC a study of QC on public comments, making them acid-fast stains, and each time of use for
failures for 304 laboratories and nearly equivalent with standards that already fluorochrome stains. The revised
15,000 commercial reagent lots exist (Table 9). False positive results requirements are justified by the
representing 21 different bacteriology have been reported in testing for M. important public health consequences
and mycology tests. QC failure rates for tuberculosis (Burman, Stone, Reeves, et of accurate and timely identification of
the reagents studied were 0.3 percent al, 1997). At the same time, the mycobacteria, including M.
overall. The individual failure rate for incidence of infection caused by other tuberculosis.
TABLE 9.—CHANGES TO MICROBIOLOGY QC REQUIREMENTS
Existing regulations New regulations (specified in this rule)
Bacteriology
Each day of use, check catalase, coagulase, beta-lactamase and oxi- (NC) Each day of use, check beta-lactamase, (other than cefinase (D))
dase reagents and DNA probes using a positive and negative control. and DNA probes using a positive and negative control.
Each week of use check bacitracin, optochin, ONPG, X, and V discs or (D) Check each batch, lot number and shipment of reagents (catalase,
strips using a positive and negative control. coagulase, and oxidase), disks (bacitracin, optochin, ONPG, X, V
and XV), stains, antisera and identification systems for positive and
negative reactivity, and graded reactivity if applicable.
Each month of use check antisera using a positive and negative control (D) Check each batch, lot number and shipment of antisera when pre-
pared or opened and once every 6 months thereafter using a posi-
tive and negative control.
Mycobacteriology
Each day of use, check iron uptake test using a positive and negative (I) Each day of use, check all mycobacteriology reagents ((NC) iron up-
acid-fast organism and check all other reagents or test procedures take test) using a positive and negative acid-fast organism.
using a positive acid-fast organism.
Each week of use check acid-fast stains using positive control .............. (I) Each day of use, check acid fast stains using a positive and nega-
tive controls.
Each week of use, check fluorochrome acid-fast stains using positive (I) Each time of use, check fluorochrome stains using positive and neg-
and negative controls. ative controls.
Mycology
Each day of use, test staining materials (lactophenol cotton blue) for in- (D) Check each batch, lot number and shipment of lactophenol cotton
tended reactivity. blue when prepared or opened for intended reactivity.
Each week of use, check biochemical tests and mycological identifica- (D) Check each batch, lot number and shipment of reagents, disks,
tion tests (germ tube) with a positive control. stains, antisera and identification systems for positive and negative
reactivity.
D = Decreased QC Testing.
I = Increased QC Testing.
NC = No change.
Methodology In estimating the cost of materials for applicable subspecialties, through

changes to the microbiology QC discussions with experts in
The number of laboratories impacted
by the QC changes for the microbiology requirements, we used information from microbiology.
subspecialties of bacteriology, several different microbiology reagent For the tests the QC changes will
mycobacteriology, and mycology manufacturers and distributors (Remel, affect, the cost of QC organisms was
includes laboratories issued a Certificate Becton Dickinson, and Fisher), considered negligible since organisms
of Compliance or a Certificate of including average list prices or may be preserved and recultivated on an
Accreditation performing testing in the suggested retail prices for reagents and ongoing basis. Although the cost of
applicable subspecialties of supplies (we acknowledge some maintaining cultures, including media
microbiology according to the CMS laboratories receive lower prices and supplies, and the time spent in
OSCAR (2001) database. The number through negotiated discounts or preservation and recultivation may be
also includes the 1,448 laboratories purchasing agreements). We estimated considerable, the changes in this final
performing testing in bacteriology, the time and amount of reagent needed rule will not cause complete elimination
mycobacteriology, and mycology to perform QC testing and maintain of QC organism testing; therefore, the
laboratories in the exempt States. records for the affected tests in the cost of culture maintenance will not
change. On the other hand, in month of use, to every 6 months after organism to be identified. However, our
mycobacteriology, negative control initial QC testing. estimates of the additional QC required
organisms are now required for and number of laboratories that these
Mycobacteriology
biochemical identification tests. changes will impact could be inflated
Although this could result in some We expect the QC changes will affect for several reasons. First, many
initial expense if new organisms must a total of 3,185 mycobacteriology mycobacteriology laboratories now use
be purchased, significant cost should laboratories in various degrees, molecular methods for organism
not be incurred, since in some cases the depending upon the services they identification in lieu of conventional
same organism may be used as a control provide. This includes 2,903 biochemical tests (we are not changing
for more than one test, and some of the laboratories in the CMS OSCAR (2001) the QC requirements for molecular
organisms used for negative controls database and 282 laboratories in exempt methods). According to an ASM survey
may be organisms already used as States. Based on estimates of the levels presented to the CLIAC in 1999, 78
positive controls for different of mycobacteriology testing performed percent of the responding laboratories
biochemical tests. in the U.S. (CDC, 1995), all performing mycobacterial identification
For estimating labor costs (the larger mycobacteriology laboratories perform used molecular methods. It is likely that
component of the QC cost for many acid-fast stains and could be impacted this percentage will increase in the
tests), we used the 2000 mean wage per by the changes to the QC requirements future as new technology continues to
hour for a staff medical technologist for this testing. However, according to be developed. Second, a significant
(Ward-Cook and Tannar, 2001), divided the estimates above, only 35.4 percent number of mycobacteriology
by 60 minutes per hour to calculate the (1,127) of mycobacteriology laboratories laboratories only identify M.
cost per minute ($0.30). The cost of perform mycobacterial organism tuberculosis and do not use biochemical
labor is the sum of the time required to identification, including 24.4 percent tests to identify additional species of
perform QC and maintain the QC that perform acid-fast stains, primary mycobacteria. Last, professional
records, multiplied by the calculated culture, and identification (at least of M. standards and at least one accreditation
wage per minute. The total cost of QC tuberculosis complex), and 11.0 percent organization already recommend or
per test is the sum of the labor and that perform acid-fast stains, primary require a negative control in addition to
material costs. culture, identification, and drug- a positive control for each identification
susceptibility testing. Therefore, this test; therefore, the increase in the
Bacteriology number represents the maximum requirement will not impact laboratories
We estimate that the QC changes for number of laboratories that could be
already meeting these standards. Since
bacteriology will affect 27,443 fully impacted by all QC changes for
sufficient data are not available to
laboratories, consisting of 26,610 this subspecialty.
laboratories in the CMS OSCAR (2001) For acid-fast stains, we are now quantify these considerations, we
database and an additional 833 requiring positive and negative control estimate a maximum of 35.4 percent of
bacteriology laboratories in exempt organisms to be QC tested each day of mycobacteriology laboratories will have
States. The changes pertain to reagents use rather than each week of use. In to perform additional QC for
commonly used to identify bacteria. addition, we are now requiring that conventional biochemical tests.
Although these reagents are primarily fluorochrome acid-fast stains be QC Mycology
used for high complexity culture and tested each time of use rather than each
identification procedures that may not week of use. Although not all We are reducing the QC testing for the
be performed in a number of physician mycobacteriology laboratories perform germ tube test by eliminating the
office laboratories or laboratories that both types of stains on a daily basis, the positive control each week of use after
perform only moderate complexity specific percentage of laboratories initial testing of positive and negative
testing, we included all bacteriology performing each type of stain is controls with every batch, lot number,
laboratories in our estimates because unavailable. We conservatively and shipment. We are also reducing the
some physician office laboratories estimated that the QC change will affect QC testing for lactophenol cotton blue
perform high complexity culture and all mycobacteriology laboratories for from checking this stain for intended
identification procedures, and at least both staining procedures and will reactivity each day of use, to requiring
one of the reagents may be used for require the laboratories to perform QC QC testing only with each batch, lot
moderate complexity tests. We realize testing for each procedure at least daily. number, and shipment. We do not
the number of bacteriology laboratories However, professional standards of expect the QC changes to affect all
that these QC changes affect may be practice recommend QC for acid-fast 18,117 laboratories performing
overestimated. stains each time of use, and the QC mycology testing (17,784 mycology
As recommended by ASM, we are changes will not impact laboratories laboratories in the CMS OSCAR (2001)
reducing QC testing to every batch, lot following these guidelines. database and 333 mycology laboratories
number, and shipment, for 10 For conventional biochemical in exempt States), since the impact of
commercial bacteriology reagents. reagents and test procedures for decreasing the QC testing will differ
Under the previous QC requirements for mycobacterial identification from among laboratories depending on the
catalase, coagulase, oxidase, and beta- culture, we are now requiring that a testing performed and the numbers of
lactamase, QC testing was additionally negative control organism be tested in positive cultures obtained by these
required each day of use. The previous addition to a positive control organism laboratories. For both the germ tube test
QC requirements for bacitracin, each day of use. Based on the and the lactophenol cotton blue stain,
optochin, ONPG, X, V, and XV strips biochemical tests used for mycobacterial we conservatively estimate that the
and disks were to test each week of use identification as listed in Essential reduction in QC testing will affect 50
after initial testing of each batch, lot Procedures for Clinical Microbiology percent of the total laboratories (9,059),
number, and shipment of reagent. For (Eisenburg, 1998), we estimate 10 those being hospital and independent
antisera (including Salmonella and additional negative controls for laboratories that would perform the high
Shigella antisera), we are reducing the biochemical tests may be performed by complexity culture procedures that
QC testing requirements from every each laboratory depending on the require the use of these reagents.
Benefits are reducing QC testing from every then determined the change in cost per
month of use to testing once every 6 day, week, and year (Table 10). In
Bacteriology
months after the initial QC testing of determining these changes, we
Reducing the QC testing requirements each batch, lot number, and shipment of considered the decrease in frequency of
for bacteriology results in a significant reagent. Assuming an average shelf life testing for each reagent (previously
decrease in costs for the laboratory, of 2 years before expiration results in daily vs. weekly vs. monthly). To
including savings in reagents, supplies, cost saving of 20 QC tests. calculate weekly changes, we used an
and labor. To estimate the impact of In addition to the direct financial average of 6 days per week for
these reductions, the QC cost associated savings in bacteriology laboratories, laboratory operations, recognizing that
with the changes must be compared to reducing the QC testing will also result while most hospital laboratories operate
the current cost of QC testing. We in a time savings equal to the time 7 days a week, physician office
assumed laboratories are currently previously required to perform the laboratories (that perform some culture
performing QC testing for each batch, lot testing and maintain QC records on a and identification procedures) may only
number, and shipment of reagents; daily, weekly, or monthly basis. This operate 5 days a week. Since we
therefore, this practice is not affected by time saving could lead to increased
these QC changes. For catalase, estimate all bacteriology laboratories use
productivity in bacteriology
coagulase, oxidase, and beta-lactamase, all tests for which QC is reduced, to
laboratories.
eliminating the daily QC requirement To calculate the savings by reducing determine the total annual savings per
results in a savings for each of these requirements for QC testing in laboratory, we added the QC savings for
tests equivalent to the cost of the daily bacteriology, we estimated the baseline each individual test.
QC. Similarly, by eliminating the expenses per laboratory for performing To estimate the total annual savings
weekly QC requirement for bacitracin, each QC test. In calculations for beta- in QC costs for all bacteriology
optochin, ONPG, X, V, and XV strips lactamase testing, as per the ASM study, laboratories, we multiplied the total
and disks, there is a savings for each of we assume laboratories use CefinaseTm annual savings per laboratory by the
these tests equivalent to the cost of the as their method of testing. After number of laboratories affected (27,443),
weekly QC. For antisera (for example, estimating the cost per individual QC and estimated a total cost savings of
Salmonella, Shigella typing sera), we test (positive and negative controls), we $62.4 million the first year.
TABLE 10.—CHANGE IN COST PER TEST FOR REVISED BACTERIOLOGY QC REQUIREMENTS

Change Change Change
Labor Reagent Reagent Total cost
Reagent in cost in cost in cost
cost* amount cost per test per day per week per year
Catalase ................................................ $0.60 1 drop ........... $0.08 $0.68 ¥$0.68 ¥$4.08 ¥$212.16
Coagulase ............................................. 0.60 2 drops ......... 0.17 0.77 ¥0.77 ¥4.62 ¥240.24
Oxidase ................................................. 0.60 1 drop ........... 0.06 0.66 ¥0.66 ¥3.96 ¥205.92
Cefinase ................................................ 0.60 2 discs .......... 2.65 3.25 ¥3.25 ¥19.50 ¥1,014.00
Bacitracin ............................................... 0.60 2 discs .......... 0.40 1.00 ¥0.17 ¥1.00 ¥52.00
Optochin ................................................ 0.60 2 discs .......... 0.33 0.93 ¥0.16 ¥0.93 ¥48.36
ONPG .................................................... 0.60 2 discs .......... 0.98 1.58 ¥0.26 ¥1.58 ¥82.16
X ............................................................ 0.60 2 strips ......... 1.60 2.20 ¥0.37 ¥2.20 ¥114.40
V ............................................................ 0.60 2 strips ......... 1.60 2.20 ¥0.37 ¥2.20 ¥114.40
XV .......................................................... 0.60 2 strips ......... 1.60 2.20 ¥0.37 ¥2.20 ¥114.40
Antisera ................................................. 0.60 2 drops ......... 6.98 7.58 ¥0.24 ¥1.46 ¥75.80
Total ............................................... .................... ...................... .................... .................... .................... .................... ¥2,273.84

* Labor cost estimate for each reagent includes one minute to perform QC test and one minute for recording and monitoring QC results.
Mycobacteriology conventional biochemical tests to financial savings will equal the cost of
identify mycobacteria, erroneous test weekly QC, and the time savings will
Erroneous test results can lead to
results can most likely be prevented by equal the time spent on a weekly basis
inaccurate diagnoses and unnecessary
including a positive and negative performing and recording QC for this
or inappropriate therapy. When this
control organism for each test each day test. For lactophenol cotton blue,
pertains to M. tuberculosis or other
of use. Although difficult to quantify, required QC testing each day of use is
mycobacteria currently emerging as
significant pathogens, it could have the increased costs for additional QC now eliminated. The cost and time
substantial cost implications or adverse testing are outweighed by the benefits of savings resulting from this reduction is
health outcomes due to the side effects prompt, accurate mycobacterial based on calculations assuming this test
of drugs used to treat infections caused detection and identification, and is performed an average of twice a week,
by these organisms. Therefore, it is appropriate therapy for mycobacterial when positive fungal cultures are
critical for laboratories to rapidly detect infections. detected.
mycobacteria and accurately identify Mycology We estimated the savings for QC
individual species within this genus. testing in mycology by determining
For laboratories performing acid-fast Reducing the QC testing requirements baseline expenses for each germ tube
and/or fluorochrome acid-fast stains, for the germ tube test and lactophenol test labor ($0.90) and materials ($0.73),
accuracy is best ensured by including cotton blue stain will result in a cost and each lactophenol cotton blue test
positive and negative controls each day and time savings for mycology labor ($0.60) and materials ($0.06),
(acid-fast) and each time (fluorochrome laboratories. Since weekly QC is followed by calculation of the weekly
acid-fast) of use. For laboratories using eliminated for the germ tube test, the and annual savings that will be realized
by reducing the QC frequency for these more than 35.4 percent of laboratories will incur an increase in QC testing
tests. Since we estimate that these perform organism identification. costs for both methods. However, some
changes will affect 50 percent of Therefore, when estimating the overall mycobacteriology laboratories use only
mycology laboratories, the total annual costs of increasing the mycobacteriology one method of staining, and some
cost savings in mycology will be the QC requirements, we considered the laboratories already check QC slides
annual savings per laboratory difference in the number of affected each time of use. The percentage of
multiplied by half the number of laboratories in the calculations. laboratories using each type of stain
mycology laboratories (9,059), an When calculating costs for the acid- exclusively or already performing QC
estimated total cost savings of $1.4 fast and fluorochrome acid-fast stains, each time of use is not available.
million the first year. we estimated that for each test, Therefore, our estimate of the cost
Costs mycobacteriology laboratories would impact of this increase in QC testing is
test two QC slides on at least a daily higher than the actual costs that will be
Mycobacteriology basis. Although QC is required each incurred. When calculating the weekly
We estimated the cost for the changes time of use for fluorochrome acid-fast QC testing costs for acid-fast stains, we
to mycobacteriology QC testing in the stains (which can differ from each day used 7 days for laboratory operations,
same manner as we estimated savings of use), we assume QC would be taking into account the CDC
for bacteriology (Table 11). However, in performed daily and that each recommended turnaround time of 24
mycobacteriology, not all laboratories laboratory performs both acid-fast and hours (Huebner, Good and Tokars, 1993)
will be affected for every test, since no fluorochrome acid-fast stains daily and for reporting acid-fast smears.
TABLE 11.—CHANGE IN COST PER TEST FOR REVISED MYCOBACTERIOLOGY QC REQUIREMENTS

Change Change Change
Labor Reagent Reagent Total cost in cost per in cost per in cost
cost amount cost per test day week per year
Identification Tests1 .......... 2 $6.00 Variable ............................ $20.46 $26.46 +$7.56 +$52.92 +$2,751.84
Acid-fast Stains ................. 3 1.80 2–3 mL of 3 solutions ....... 0.61 2.41 +2.41 +14.46 +751.92
Fluorochrome Stains ......... 3 1.80 2–3 mL of 3 solutions ....... 0.60 2.40 +2.40 +14.40 +748.80
Total ........................... .................... ........................................... .................... .................... .................... .................... +4,252.56

1 Estimateincludes the following tests: arylsulfatase, 68 degree catalase, semi-quantitative catalase, NaCl tolerance, niacin, nitrate,
pyrazinamidase, tellurite reduction, Tween 80 hydrolysis, and urease.
2 Combined labor cost estimate for each reagent/test includes one minute to perform QC test and one minute for recording and monitoring QC
results.
3 Labor cost estimate for each stain procedure includes five minutes to perform QC test and one minute for recording and monitoring QC
results.
For conventional biochemical costs. Since in most laboratories these laboratories participating in the study
reagents and identification procedures tests are performed less frequently than translated into one failure for all
used on mycobacterial culture isolates, acid-fast stains or bacteriology reagents surveyed every 53 years (ASM,
we calculated the potential cost increase identification tests, our estimates 1996). Since in many cases, a single
for adding a negative control to each test assume that each of these tests would be reagent or test is only a part of a
based on 10 biochemical reagents (or run twice per week. The additional cost bacterial identification scheme, these
tests) used for mycobacterial for each laboratory per week is equal to rare failures are not likely to lead to
identification, as listed in Essential twice the total cost for all 10 tests, and errors in organism identification or
Procedures for Clinical Microbiology the additional annual cost per patient testing.
(Eisenburg, 1998). Although several laboratory is estimated on the basis of
Mycology
additional biochemical tests can be used this total weekly cost.
in the conventional scheme of To estimate the total annual increase We expect no additional errors as a
mycobacterial identification, most of in the cost of QC for mycobacteriology, result of the decreased requirements for
these tests were not included in our we multiplied the increased costs for QC in mycology.
calculations since they are growth tests acid-fast and fluorochrome stains by the
total 3,185 mycobacteriology Scope of Impact
on certain selective media, which would
not be subject to increased QC laboratories, and multiplied the The changes in QC requirements for
requirements. The iron-uptake test was increased costs for conventional microbiology laboratories will result in
also not included in our calculations biochemical identification tests by 35.4 significant cost savings overall, on an
since a negative control was previously percent of the total number of annual and 5-year basis, when
required for this test. In estimating the laboratories (1,127), and then added considering the net effect of the changes
change in cost for these identification these amounts. We estimated the total being implemented in the subspecialties
procedures, the cost of labor for these cost increase would be $7.9 million the of bacteriology, mycobacteriology, and
tests was first calculated for a single test first year. mycology. The decreased QC
and then multiplied by 10. We assume Error Rates requirements in bacteriology and
the same approximate time is required mycology are expected to impact all
to perform and record each QC test. The Bacteriology U.S. laboratories performing this testing
total reagent cost was determined by We do not expect increased error rates under a Certificate of Compliance,
adding the cost of reagents for each in patient testing for the QC changes in Certificate of Accreditation, or State
individual test. The total cost for all 10 bacteriology. As reported in the ASM exemption. We estimate the total cost
tests is the sum of the labor and reagent study, the QC failure rates for savings for each microbiology laboratory
performing bacteriology testing to be the next 5 year estimate of $34.6 million b. Changes in Required QC Frequency
$2,274 the first year. By multiplying this are likely inflated to some degree. for Syphilis Serology, Immunology, and
number by the total number of To summarize, the total savings in QC Hematology
bacteriology laboratories (27,443), we testing costs that will result from the Syphilis Serology
estimate the total savings for changes in the microbiology
bacteriology laboratories to be $62.4 We estimated that the reduction in
requirements is the sum of the savings frequency for syphilis serology QC
million the first year and the overall in the subspecialties of bacteriology and
savings over the next 5 years to be testing may affect 7,634 laboratories
mycology, minus the cost increases in (Certificate of Compliance (3,068),
approximately $273.7 million for
the subspecialty of mycobacteriology, a Certificate of Accreditation (4,070), and
bacteriology.
For mycology, we estimate the total minimum total cost savings for State-exempt (496)) (OSCAR, 2001 and
cost savings the first year per laboratory microbiology laboratories of $55.9 the States of New York and
will be $153, and the change will affect million the first year. The savings Washington). Laboratories will be
9,059 mycology laboratories with total projected over the next 5 years are required to run controls each day
savings of $1.4 million. We estimate approximately $245.2 million. patient specimens are tested, rather than
overall savings will be $6.1 million for Alternative Approaches each time they are tested. For
the next 5 years. laboratories testing patient specimens
Although the increase in QC For bacteriology and mycology, one more than once a day, this change will
requirements for mycobacteriology will alternative approach would be to result in a cost savings. However, we
result in increased costs for continue to require QC testing for all cannot estimate the amount of savings,
microbiology laboratories conducting reagents at the same frequencies as because we do not know how many of
this testing, the impact will not affect all specified in the February 1992 these laboratories conduct testing more
laboratories to the same extent, as regulations. However, there are no data than once per day.
previously explained. In fact, that support continuing these Immunology
laboratories previously following frequencies to ensure the quality of
professional standards of practice for patient testing. We believe if the There are a total of 20,665 laboratories
mycobacteriology will not be impacted previous frequencies were maintained, (Certificate of Compliance (9,728),
at all by these QC changes. the total financial costs in labor and Certificate of Accreditation (10,285),
Mycobacteriology laboratories will and State-exempt (652)) performing
materials would far exceed the possible
likely incur increased QC costs for acid- immunology testing that may be affected
benefits in detecting problems with
fast and/or fluorochrome stains, an by the reduction in the frequency for
reagents. Another approach we
estimated maximum increase of $1,501 immunology QC testing. Under this
considered is QC testing less frequently
per laboratory the first year, and $4.8 final rule, laboratories must perform
than with every batch, lot number and
million overall, assuming laboratories control procedures each day of testing,
shipment of reagents (catalase,
use both methods of staining, and did rather than concurrent with each testing
coagulase, beta-lactamase, oxidase, and
not previously test controls each time of event. We do not know how many of
germ tube test), disks and strips
use. Since only 35.4 percent of these laboratories test patient specimens
(bacitracin, optochin, ONPG, X, V, and
mycobacteriology laboratories perform more than once per day for each
XV), stains (lactophenol cotton blue),
organism identification, the impact of immunology procedure; therefore, we
and antisera. However, because damage
increasing the QC requirements for cannot estimate the cost savings if
or improper handling of each batch, lot,
certain identification tests will affect control procedures are performed less
or shipment can result in compromised
significantly fewer laboratories. We frequently. However, these provisions
reagent integrity, we did not consider
calculated this increase to cost $2,752 for the frequency of control testing do
this to be acceptable. We also
per laboratory the first year, with a not supercede manufacturers’
considered leaving the requirement for
maximum cost of $3.1 million overall. instructions or laboratory specifications
monthly testing of antisera in place, but
However, as explained previously in the that may require control testing more
since there are no data to support this
Mycobacteriology subsection of the frequently; for example, each time
frequency, and the ASM data showed
Methodology section, we believe this patient specimens are tested.
the reagents are relatively stable, we
cost impact is overestimated for the
considered QC testing every 6 months Hematology
increased QC for biochemical
adequate for these relatively expensive For hematology, we are reducing the
identification tests. Evidence shows that
reagents with extended shelf lives. required frequency for control testing
with newer technology, fewer
laboratories use the older conventional For mycobacteriology, we considered from once each 8 hours of operation to
tests, and this is expected to further not requiring a negative control with once each day of testing. There are a
decrease as technology continues to daily use of identification reagents, and total of 32,753 laboratories (Certificate
improve. In addition, laboratories not requiring QC daily for acid-fast of Compliance (16,332), Certificate of
offering limited services may not use as stains, and each time of use for Accreditation (15,477), and State-
many biochemical identification tests if fluorochrome stains. However, the exempt (944)) that perform hematology
they only identify a limited number of expense of increasing these testing to which this change may apply.
organisms. Last, since professional requirements is relatively small because We do not know the exact number of
standards and an accreditation so few laboratories are impacted and in laboratories that this change will affect
organization already recommend or practice the incremental impact of because this change will only impact
require negative control organisms, adding a second control is relatively laboratories performing testing longer
many laboratories may already be small. We cannot quantify the impact on than 8 hours per day. However, we
including the controls we are now error rates of not implementing these expect it will affect most hospital
requiring in this regulation. Therefore, changes, but false positive tests in laboratories and many independent
the combined annual estimate of mycobacteriology can result in laboratories, since the majority of
increased QC costs for mycobacteriology considerable extra expense in patient hospitals and independent laboratories
laboratories of $7.9 million overall and care. operate 24 hours per day. For these
laboratories, if manufacturer extensive knowledge, training, and laboratories with each certificate type
instructions and laboratory experience to perform the management have remained stable over the past
specifications allow, performance of two and administrative duties necessary to several years; however, the absolute
control testing events per day can be ensure that personnel are competent, numbers show trends toward lower
eliminated for each hematology methodologies are appropriate, and the complexity levels (waiver and PPM).
analyzer. Therefore, the aggregate quality control and quality assessment While we expect this trend to continue
savings may be significant, but we programs are suitable for the testing in the future because of the widening
cannot estimate the impact. performed. The high complexity availability of waived tests, we assume
laboratory director qualification that COC laboratories switching to
Alternative Approaches
requirements in this final rule balance waiver and PPM certificates are those
For these three changes, the aggregate the quality concerns with the need to that perform only moderate complexity
impact will be a cost savings; however, ensure continued access to high testing and the number of COC
we have insufficient information to complexity testing. laboratories performing some high
estimate the reduced burden or savings complexity testing will remain stable. In
in reduced analyst time, cost of Methodology
addition, we assume the number of
reagents, and control materials To determine the impact of these accredited laboratories performing some
associated with the reduced frequency laboratory director qualification high complexity testing will remain
of control material testing. We requirements over time on laboratories fairly stable, as has been the trend in the
considered leaving the requirements for performing high complexity testing, we past several years.
control procedures unchanged; estimated the number of high
however, based upon the current complexity laboratories potentially High Complexity Laboratory Director
stability of the test systems used in impacted and the number of qualified Demographics
these three areas, we have determined individuals available to serve as high We also used the OSCAR (2001)
that few additional testing errors would complexity laboratory directors during database to identify the CLIA
be prevented by more frequent control the next 5 years. qualification requirements by which
testing. those individuals currently serving as
Laboratory Demographics
laboratory directors of COC high
4. Completion of Laboratory Director Using the CMS OSCAR (2001) complexity laboratories qualified. Using
Phase-in database, we have determined that this data, we have calculated that 28
We are completing the phase-in approximately 8,000 of the 22,720 percent of these laboratories are directed
qualification requirement for high Certificate of Compliance (COC) by board-certified pathologists; 56
complexity laboratory director that laboratories (35 percent, or 4.7 percent percent by licensed physicians with
allows individuals with a doctoral of all CLIA laboratories) perform some laboratory training or experience; 5
degree to qualify based on training and high complexity testing. To determine percent by individuals with doctoral
experience in lieu of board certification. the total number of Certificate of degrees; 3 percent by individuals who
With the implementation of this final Accreditation (COA) laboratories that have been serving as laboratory
rule, board certification will be required perform high complexity testing, we directors and were qualified as a
under one provision. However, under included the approximately 9,200 laboratory director on or before
the second provision, we are allowing laboratories accredited by five of the February 28, 1992 (according to the
individuals, who qualified under the CLIA-approved accreditation March 14, 1990 final rule with comment
phase-in provision and who have served organizations (American Association of period (55 FR 9538) published in the
or are now serving as directors of Blood Banks, American Osteopathic Federal Register); 7 percent by
laboratories performing high complexity Association, American Society for individuals who on or before February
testing and have at least 2 years of Histocompatibility and 28, 1992 were qualified under State law
training or experience, or both, and 2 Immunogenetics, College of American to direct a laboratory in the State in
years of experience directing or Pathologists, and Joint Commission on which the laboratory was located; and
supervising high complexity testing to Accreditation of Healthcare less than 1 percent by individuals who
continue to serve as laboratory directors. Organizations). The majority of these meet the qualifications currently at
To ensure a smooth transition to the laboratories are independent or § 493.1443(b)(6) for the subspecialty of
new provisions for directors of high hospital-based and are assumed to oral pathology.
complexity testing who are not board perform some high complexity testing. We assume individuals currently
certified (but who have doctoral We also estimated that approximately serving as high complexity laboratory
degrees), we will not be holding 1,700 of the 6,881 COLA-accredited directors will retire at approximately the
facilities out of compliance with the laboratories (25 percent) perform some same rate as projected for the general
provisions of the rule concerning high complexity testing. In addition, the population; that is, on average 3.8
directors who are not board certified number of high complexity laboratories percent per year for fiscal years 2001
until the effective date of this new rule, in the two CLIA-exempt States, New through 2005 (U.S. Office of Personnel
to the extent the facilities are otherwise York (540) and Washington (235), is Management, Central Personnel Data
in compliance with the requirements for approximately 775 laboratories (New Files, 2000). Therefore, we anticipate
laboratory directors. York and Washington, personal 3.8 percent of the approximately 19,700
communication, March 2002). high complexity laboratories (750) will
Rationale Therefore, the total number of CLIA need to hire a new laboratory director
Personnel qualifications are laboratories (including New York and each year for the next 5 years. Pool of
considered an essential benchmark of Washington) performing some high Individuals Qualified to Serve as High
performance and requiring appropriate complexity testing in the United States Complexity Laboratory Directors.
qualifications for the complexity level of is estimated to be approximately 19,700 Using data (September 2000) from the
testing performed by the laboratory is in laboratories. American Board of Medical Specialties
the best interest of quality testing. High As previously mentioned and (ABMS), we estimated the total number
complexity testing requires more illustrated at Table 4, the percentages of of physicians that have 1 year of
laboratory training during medical laboratory directors and have at least 2 (from receipt of the specimen through
residency to be 17,400. In addition, years of training or experience, or both, test performance, test reporting and
ABMS reports 5,784 pathologists and 2 years of experience directing or systems’ assessments), eliminates
received board certification over the supervising high complexity testing to duplicative requirements, and rewords
past 10 years. This number is consistent continue in their capacity without certain requirements. In response to
with the Accreditation Council for obtaining board certification. This comments received to previous
Graduate Medical Education’s (ACGME) provision circumvents the costly and rulemakings, wherever possible we have
data indicating there are approximately disruptive burdens associated with made changes to the regulations to
2,660 anatomical and clinical pathology currently employed individuals reduce the burden and expense to
residents enrolled through the current obtaining board certification and laboratories. Also, in recognition of new
academic year (ending June 2002). laboratories, which perform high and emerging technologies and
These residents will be eligible for complexity testing, replacing currently methodologies, obsolete requirements
board certification over the next 4 years. serving directors. have been deleted and a few new
The total number of board-certified With regard to future impact, requirements have been added. Listed
doctoral-degreed individuals is available data indicate there are ample below are several of these revisions, not
estimated to be 2,090 (American Board numbers of qualified individuals yet discussed in this impact analysis,
of Bioanalysis (ABB), American Board available to fill the estimated annual which may result in some change in
of Clinical Chemistry (ABCC), American high complexity laboratory director costs or burden for laboratories. While
Board of Forensic Toxicology (ABFT), vacancies over the next 5 years. In we believe the change in costs or
American Board of Medical Genetics addition, the CLIA regulations permit burden, or both, will be relatively
(ABMG), American Board of Medical qualified individuals to direct up to five minor, lack of data and information
Laboratory Immunology (ABMLI), laboratories, which may further lessen makes these estimates either difficult or
American Board of Medical the burden associated with replacing impossible to quantify.
Microbiology (ABMM), and National retiring laboratory directors. However,
Registry of Certified Chemists (NRCC)). States and accrediting organizations Revisions Resulting in No Change in
In addition, one HHS-approved board may have more stringent qualification Burden and Costs
reports an average of 8 individuals requirements for laboratory directors The FDA QC review process was
receiving certification annually, another and affected laboratories would need to intended to be implemented when the
board reports an average of 11 annually, continue to meet these requirements. QC phase-in ended, but we established
and a third board reports 37 annually Costs through our survey process that the
(AAB, ABCC, ABFT, ABMLI, ABMM, review would be not be of benefit to
NRCC, personal communication, March The provisions in this final rule at laboratories. Because this review was
2002). § 493.1443(b)(3), will have no not implemented, there is no impact.
Based on the data provided by the immediate costs, and we believe the
• Records of test system performance
HHS-approved boards, ABMS, and costs over the next 5 years will be no
specifications established or verified as
ACGME, we believe there will be a greater than the costs laboratories
required under § 493.1253 must be
sufficient number of individuals performing high complexity testing
retained for the period of time the test
available to fill the possible 750 high currently experience when replacing
system is in use. Because this
complexity laboratory director directors.
information provides important data
vacancies per year over the next 5 years. Alternative Approaches about the laboratory’s test system
Moreover, only 5 percent of the COC performance (for example, accuracy,
In the December 28, 2001 proposed
high complexity laboratories currently precision, and reportable range of
rule, we considered qualifying
employ a laboratory director with a patient results) that the laboratory is
individuals with a doctoral degree and
doctoral degree. We believe the required (formerly at § 493.1109(g), now
6 years of laboratory training and
percentage of COA and Washington at § 493.1291(e)) to provide to clients
experience, or both (including 2 years
State high complexity laboratories upon request, laboratories should have
experience directing or supervising high
employing a laboratory director with a already been maintaining this
complexity testing), as directors of
doctoral degree may be about the same information. Therefore, there is no
laboratories performing high complexity
or lower. Therefore, we estimate that additional burden with this change.
testing. While we offered this as an
approximately 180 of the 958 COC, • When a laboratory transcribes or
alternative qualification pathway, we
COA, and Washington State high enters test requisition or authorization
agree with the majority of commenters
complexity laboratories that employ a information into a record or information
and the CLIAC recommendation that the
doctoral-degreed individual as a system, it must ensure that the
provision is not commensurate with the
laboratory director may have to replace information is transcribed or entered
responsibilities of a high complexity
their director during the next 5 years (36 accurately. Formerly at § 493.1701,
laboratory director or consistent with
annually). We did not include the high laboratories were responsible for
the qualification requirements and
complexity laboratories in New York identifying and correcting problems and
responsibilities specified for the other
because they require laboratory ensuring accurate, reliable, and prompt
CLIA laboratory personnel categories.
directors to have ‘‘specific’’ training or reporting of test results. Inaccurate
Moreover, we have determined that this
experience in the specialty(ies) of transcription of test requisition or
qualification pathway is not needed to
testing the laboratory performs. authorization information would be one
ensure a sufficient pool of qualified
Benefits individuals to serve as high complexity example of a problem, if left
laboratory directors and thus continued uncorrected, that could interfere with
Impact both the reporting of test results and the
access to high complexity testing.
There will be no immediate impact accuracy of the results. For this reason,
because the second provision included 5. Miscellaneous Changes we believe this new requirement should
in this final rule allows individuals who The reorganization of this final rule have no impact on the laboratory’s
have served or are currently serving as reflects the flow of laboratory testing burden or costs.
• Section 493.1254 now specifies that will be an ongoing factor in determining As a consequence of this, a portion of
when using unmodified manufacturer’s appropriate screening frequencies. those laboratories receiving ungraded
equipment, instrument or test systems, • For the performance of non-renal PT results may have failed to recognize
the laboratory must follow the transplantation in an emergency that their actual PT performance was
manufacturer’s instructions for situation, we are eliminating the not acceptable and only realized that
maintenance and function check requirement that the results of final their performance was unacceptable
protocols rather than establish its own. crossmatches be available before the when their PT results were reviewed as
While this revision results in a less transplantation when the recipient part of an inspection. Thus, in some
stringent requirement than that demonstrates presensitization by prior instances laboratories failed to make
specified under former § 493.1215, we serum screening. In this final rule at appropriate corrections to testing
do not anticipate a change (decrease) in § 493.1278(f)(3) (formerly at problems, identified by unacceptable PT
burden or costs to the laboratory § 493.1265(b)(3)), the laboratory must performance, in a timely manner. Now
because following the manufacturer’s have available, and follow, policies that at §§ 493.911(c)(1), 493.913(c)(1),
instructions for maintenance and address when HLA testing and final 493.915(c)(1), 493.917(c)(1),
function checks when using unmodified crossmatches are required for 493.919(c)(1), 493.923(b)(1),
equipment, instruments, or test systems presensitized non-renal transplant 493.927(c)(1), 493.931(c)(1),
was acceptable practice for meeting the recipients. We cannot estimate the 493.933(c)(1), 493.937(c)(1), and
former requirement. savings from this reduction. 493.941(c)(1), the consensus agreement
• In the specialty of Revisions for Which There May Be a requirement is lowered to 80 percent.
histocompatibility now at § 493.1278, Negligible Increase in Burden or Costs Fewer PT results will be ungraded and
the laboratory’s reagent typing inventory • The laboratory must ensure a uni- a portion of those laboratories
must indicate reagent specificity as well directional workflow for molecular previously not graded due to a lack of
as the previously required source, amplification systems that are not consensus will receive an unacceptable
bleeding date and identification contained in enclosed systems. This PT grade. Thus, these laboratories will
number, and volume remaining. includes maintaining physically be alerted to potential testing problems
Indicating a reagent’s specificity in the separate areas for specimen preparation, sooner. Also, with the change at
laboratory’s reagent inventory is routine amplification and product detection and § 493.1236(b)(2), which now requires all
laboratory practice that was reagent preparation, as applicable. This laboratories to verify testing accuracy
inadvertently not addressed in the is a recommended guideline for good for any analyte, subspecialty, or
regulations. This new requirement for laboratory practice by several laboratory specialty assigned a PT score that does
documentation of reagent specificity professional organizations. Although we not reflect the laboratory’s actual PT
will have no impact on the laboratory’s are unable to estimate the number of performance, an additional number of
burden or costs. laboratories that perform molecular laboratories may become cognizant of
Revisions Resulting in a Decrease in amplification with open systems their poor testing performance sooner
Burden or Costs. without following the recommended than when PT results are not graded and
guideline, we expect the number to be they receive an acceptable score by
• We are eliminating the requirement small and any increase in burden or cost default. The combination of fewer
under the specialty of with meeting this new requirement, ungraded PT results with the
histocompatibility for each individual now at § 493.1101, negligible. requirement for all laboratories to
performing testing to evaluate • If the laboratory ceases operation, it review and verify their PT results,
previously tested specimens monthly as must make provisions to ensure that all especially when they are deemed
specified formerly at § 493.1265. The records, slides, blocks, and tissues are questionable by the PT program, will
mechanism for and frequency of maintained for the applicable time result in these laboratories, in a more
competency assessment of frames. We anticipate that this change timely manner, identifying and
histocompatibility testing personnel now at § 493.1105 will affect few correcting potential sources of error
will now be determined, as it is in all laboratories; however, we cannot which may not have been otherwise
other laboratory specialties and estimate the number or associated cost. detected, thereby increasing overall
subspecialties, by the laboratory’s • In the former requirements at laboratory accuracy. However, there
technical consultant or supervisor under §§ 493.911(c)(1), 493.913(c)(1), may be some burden for those
§§ 493.1413(b)(8) and (9) and 493.915(c)(1), 493.917(c)(1), laboratories that are now required to
493.1449(b)(8) and (9), respectively. 493.919(c)(1), 493.923(b)(1), verify testing accuracy but are having no
Although this is a reduction in burden, 493.927(c)(1), 493.931(c)(1), real problem with testing. Since
we cannot estimate the cost savings. 493.933(c)(1), 493.937(c)(1), and verifying testing accuracy whenever
• For laboratories performing 493.941(c)(1) PT programs were there is a potential likelihood of error is
histocompatibility testing, we are required to grade PT results by first generally regarded as good laboratory
eliminating the specified frequencies for comparing the laboratory’s response to practice, and in most instances the
screening potential transplant recipient the response which reflects agreement laboratory’s routine use of QC may be
sera for performed HLA–A and B of either 90 percent of 10 or more used to verify testing accuracy, this
antibodies (formerly at referee laboratories or 90 percent or should not be considered burdensome.
§ 493.1265(a)(8)(i)). Instead, in this final more of all participating laboratories. If Likewise, PT programs may be slightly
rule at § 493.1278(d)(5), we are requiring this consensus agreement requirement inconvenienced by the need to change
the laboratory to have available and was met, then the results could be their grading algorithms to
follow a policy, consistent with clinical graded based on their values relative to accommodate the 80 percent consensus
transplant protocols, for the frequency the established correct response for each requirement. However, it is the
of such antibody screening. While this PT analyte, subspecialty, or specialty. If responsibility of PT programs to assist
is most likely a reduction in burden, we the consensus requirement was not met, laboratories in assessing their testing
cannot estimate the cost savings, since then laboratories were not graded and performance by providing PT samples
emerging data and research information received an acceptable score, by default. that can be appropriately graded.
Although these changes may affect sex determination and should be ‘‘Impact of quality control on accuracy in
laboratories and PT programs, the eliminated from the cytogenetics enzyme immunoassay testing for human
impact is not quantifiable and is laboratory test menu. Several laboratory immunodeficiency virus type 1
considered minor compared to the antibodies.’’ Archives of Pathology and
professional organizations consider sex
Laboratory Medicine 122, 8 (1998), pp.
overall beneficial effect of improved determination by full chromosome 700–707.
laboratory testing accuracy. analysis the standard for good Burman, William J., B.L. Stone, Randall R.
• Test requisitions or other written or laboratory practice; therefore, we added Reves, et al. ‘‘The incidence of false-
electronic authorizations for testing this requirement. Although we are positive cultures for Mycobacterium
must include the patient’s sex and age unable to estimate the number of tuberculosis.’’ American Journal of
or date of birth as specified now at cytogenetics laboratories that perform Respiratory and Critical Care Medicine,
§ 493.1241. We expect a negligible sex determination other than by full 155,1 (1997): pp. 321–326.
increase in burden or cost because the Bureau of Labor Statistics. Occupational
chromosome analysis, we expect the
patient’s age or date of birth was Outlook Handbook, 2000–2001 edition.
number to be small and any increase in Centers for Disease Control and Prevention.
required for Pap smears, formerly at burden or cost with meeting this Laboratory practices for diagnosis of
§ 493.1105(e), and most laboratories are requirement negligible. tuberculosis—United States, 1994.
already obtaining the patient’s gender, • The requirements for the test report Morbidity and Mortality Weekly Report
since it is frequently necessary for (formerly at § 493.1109, now at 1995, 44:587–590.
appropriate test interpretation (as § 493.1291) must include the patient’s Eisenberg, Henry D., Ed. Essential Procedures
required formerly at § 493.1105(f)). The name and identification number, or for Clinical Microbiology (Chapter 4.8
number of laboratories that have not unique patient identifier and Mycobacteriology—Identification
been requesting the patient’s gender and Procedures from Culture, pp. 195–196),
identification number; the test report
age or date of birth is unknown. ASM Press, Washington, D.C., (1998).
date; and if appropriate, the specimen Hoerger Thomas J., Jennifer L. Eggleston,
• The laboratory must use a control source. These are standard practices in Richard C. Lindrooth, and Emek Basker.
system capable of detecting reaction most laboratories and the impact on ‘‘Background report on the clinical
inhibition when performing molecular burden or cost is expected to be minor. laboratory industry. Final report.’’ June
amplification procedures in which In accordance with Executive Order 1997. Prepared by Centers for Economic
inhibition is a significant source of false 12866, this regulation was reviewed by Research, Research Triangle Institute,
negative results. This is a recommended the Office of Management and Budget. Research Triangle Institute, NC.
guideline for good laboratory practice by Huebner, Robin E., Robert C. Good, and
several laboratory professional References Jerome I. Tokars. ‘‘Current practices in
organizations and is now specified at Accreditation Committee for Graduate mycobacteriology: results of a survey of
§ 493.1256(d)(3)(v). While we are unable Medical Education, ‘‘Number of all state public health laboratories.’’ Journal of
to estimate the incidence of reaction programs for a specific academic year Clinical Microbiology 31, 4 (1993), pp.
Ending June 30, 2002.’’ <http:// 771–775.
inhibition or number of laboratories
www.acgame.org/adspublic/reports/ Institute of Medicine (IOM), Committee on
performing molecular amplification Medicare Payment Methodology for
procedures without following the accredited_programs_all.asp>. (April 23,
2002). Clinical Laboratory Services. (2000).
recommended guideline, we expect the Ambulatory Sentinel Practice Network Medical Laboratory Payment Policies, Now
number to be small and any increase in (ASPN). Laboratory Medicine and in the Future (Appendix D).
burden and/or cost with meeting this Questionnaire (Appendices 1 and 2) 1996. Washington, DC: National Academy Press.
new requirement negligible. Unpublished data. LaBeau, Kathleen M, Marianne Simon and
• The laboratory must check American Association for Clinical Chemistry. Steven J. Steindel. ‘‘The Pacific Northwest
immunohistochemical stains for ‘‘Quality Assurance Alternatives for Laboratory Medicine Sentinel Monitoring
positive and negative reactivity each POCT.’’ Audioconference, February 4, Network.’’ Final Report of the Findings of
time of use. Although this is an increase 1999. Questionnaire II, Test Volume and Menu
American Board of Medical Specialties. Changes: 1997–1999.’’ July 1999.
from the requirement (formerly at
‘‘General Certificates Issued 1991–2001, NCCLS Guideline EP 6–P. Evaluation of the
§ 493.1259, now at § 493.1273(a)) to linearity of quantitative analytical
Table 2.’’ September 2000. <http://
check special stains for positive www.abms.org/statistics.asp> (April 16, methods; proposed guideline. (1999).
reactivity, we cannot estimate the 2002). Villanova, PA: NCCLS.
laboratory impact because we do not American Board of Medical Specialties. NCCLS Document EP 15–P. User
know the number of laboratories that ‘‘Geographic Distribution of Diplomats by demonstration of performance for precision
perform immunohistochemical stains or Speciality Certificate.’’ September 2002. and accuracy; proposed guideline. (1998).
how often the staining is performed. We <http://www.abms.org/statistics.asp> Villanova, PA: NCCLS.
expect this change to affect a small (April 16, 2002). NCCLS Document C 28–A. How to define
number of laboratories, and the increase American Medical Association, Center for and determine reference intervals in the
Health Policy Research, ‘‘Physician clinical laboratory; approved guideline.
in burden and costs will be small. (1995). Villanova, PA: NCCLS.
socioeconomic statistics,’’ 2000–2002
• In the specialty of clinical edition, 2001. Online Survey and Certification Reporting
cytogenetics, sex determination must be American Society for Microbiology. ‘‘Survey System (OSCAR). (Electronic database).
performed by full chromosome analysis. of quality control failures in the clinical (2001). Baltimore, MD: Centers for
Formerly, in clinical cytogenetics at microbiology laboratory.’’ Report by Medicare & Medicaid Services. (Producer
§ 493.1267(a) (now at § 493.1276(c)), full Brenda McCurdy to the Clinical Laboratory and Distributor).
chromosome analysis was only required Improvement Advisory Committee, Steindel, Stephen J., William J. Rauch,
as a confirmatory test when the September 25, 1996. Marianne K. Simon, and James Handsfield.
laboratory obtained atypical results on X American Society for Microbiology. ‘‘ASM ‘‘National Inventory of Clinical Testing
and Y chromatin counts. Several benchmarking survey, microbiology Services (NICLTS): development and test
productivity ‘‘99.’’ Report by Roberta Carey distribution for 1996.’’ Archives of
commenters stated that due to the to the Clinical Laboratory Improvement Pathology and Laboratory Medicine 124,
frequency of mosaicism in individuals Advisory Committee, September 22, 1999. (2000), pp. 1201–1208.
with sex chromosome anueploidy, Barr Astles, John R., Harvey B. Lipman, William Tershakovec, Andrew M., S. Diane Brannon,
body and ‘‘Y’’ body analysis is no longer O. Schalla, Sharon O. Blummer, Ronald F. Michael J. Bennett, and Barbara M.
considered the standard of practice for Feld, Charlene Smith, Thomas L. Hearn. Shannon. ‘‘The cost of implementation of
the Clinical Laboratory Improvement this includes test systems exempt from § 493.45 [Amended]
Amendments of 1988—the example of FDA premarket clearance or approval. 7. In § 493.45(c)(3), remove the
pediatric office-based cholesterol
screening.’’ Pediatrics 96, 2 (1995), pp.
* * * * * reference to ‘‘subpart P’’.
230–234. Reportable range means the span of
test result values over which the § 493.47 [Amended]
Ward-Cook, K., and Suzanne Tannar. ‘‘2000
wage and vacancy survey of medical laboratory can establish or verify the 8. Amend § 493.47 as follows:
laboratories.’’ Laboratory Medicine 32, 3, accuracy of the instrument or test a. In paragraph (c)(2), remove the
(2001), pp.124–138. system measurement response. reference to ‘‘subpart P’’.
U.S. Government, Office of Personnel * * * * * b. In paragraph (c)(3), remove the
Management, Central Personnel Data File. Test system means the instructions cross reference to ‘‘§ 493.1776’’ and add,
‘‘Retirement Projections, Fiscal Years in its place, ‘‘§§ 493.1773 and
and all of the instrumentation,
2001–2005.’’ http://www.opm.gov/feddata/ 493.1775’’.
retire/rs-projections.pdf. (April 16, 2002). equipment, reagents, and supplies
needed to perform an assay or § 493.49 [Amended]
List of Subjects in 42 FR Part 493 examination and generate test results.
9. In § 493.49(a)(3), remove the
Grant programs—health, Health * * * * * reference to ‘‘subpart P’’.
facilities, Incorporation by Reference,
§ 493.3 [Amended]
Laboratories, Medicaid, Medicare, Subpart F—General Administration
Reporting and recordkeeping 3. Amend § 493.3, as follows:
a. In paragraph(b)(3), remove the § 493.643 [Amended]
requirements.
words ‘‘National Institutes on Drug 10. In § 493.643(c)(3)(ix), add the
For the reasons set forth in the
Abuse (NIDA)’’ and add, in their place, word ‘‘Clinical’’ before the word
preamble, the Centers for Medicare &
the words ‘‘Substance Abuse and ‘‘Cytogenetics’’.
Medicaid Services is amending 42 CFR
Mental Health Services Administration
Chapter IV part 493 as set forth below: Subpart H—Participation in Proficiency
(SAMHSA)’’.
PART 493—LABORATORY b. In paragraph (b)(3), remove the Testing for Laboratories Performing
REQUIREMENTS word ‘‘NIDA’’ and add, in its place, the Nonwaived Testing
word ‘‘SAMHSA’’.
1. The authority citation for part 493 11. Revise the heading of Subpart H
continues to read as follows:
§ 493.20 [Amended] to read as set forth above.
Authority: Sec. 353 of the Public Health
3a. Amend § 493.20, as follows: § 493.801 [Amended]
Service Act, secs. 1102, 1861(e), the sentence
a. In paragraph (b), remove the
reference to ‘‘subpart P’’. 12. In § 493.801(a)(2)(ii), remove the
following sections 1861(s)(11) through
b. In paragraph (b), remove the cross cross reference to ‘‘§ 493.1709’’ and add,
1861(s)(16) of the Social Security Act (42
U.S.C. 263a, 1302, 1395x(e), and the sentence reference to ‘‘§ 493.1777’’ and add, in its in its place, ‘‘§ 493.1236(c)(1)’’.
following 1395x(s)(11) through 1395x(s)(16)). place ‘‘§§ 493.1773 and 493.1777’’. § 493.803 [Amended]
c. In paragraph (c), remove the cross
Subpart A—General Provisions reference to ‘‘§§ 493.15(e) and 13. In § 493.803(a), remove the words
493.1775’’ and add, in its place, ‘‘tests of moderate complexity
2. In § 493.2, the introductory text is ‘‘§§ 493.15(e), 493.1773, and 493.1775’’. (including the subcategory) and/or high
republished, and the following complexity’’ and add, in their place, the
definitions are added in alphabetical § 493.25 [Amended] words ‘‘nonwaived testing’’.
order to read as follows: 4. Amend § 493.25 as follows: § 493.807 [Amended]
a. In paragraph (b), remove the
§ 493.2 Definitions 14. Revise the heading of §493.807 to
reference to ‘‘subpart P’’.
As used in this part, unless the b. In paragraph (c), remove the read as follows:
context indicates otherwise— reference to ‘‘subpart
§ 493.807 Condition: Reinstatement of
* * * * * P’’. laboratories performing nonwaived testing.
Calibration means a process of testing c. In paragraph (c), remove
and adjusting an instrument or test ‘‘§ 493.1777’’ and add, in its place, Subpart I—Proficiency Testing
system to establish a correlation ‘‘§§ 493.1773 and 493.1777’’. Programs for Nonwaived Testing
between the measurement response and d. In paragraph (d), remove the
the concentration or amount of the reference to ‘‘subpart P’’. 15. Revise the heading of subpart I to
substance that is being measured by the e. In paragraph (d), remove the cross read as set forth above.
test procedure. reference to ‘‘§§ 493.15(e) and
493.1775’’ and add, in its place, §§ 493.911, 493.913, 493.915, 493.917,
Calibration verification means the 493.919, 493.923, 493.927, 493.931, 493.933,
‘‘§§ 493.15(e), 493.1773, and 493.1775’’.
assaying of materials of known 493.937, and 493.941 [Amended]
concentration in the same manner as Subpart C—Registration Certificate, 16. In §§ 493.911(c)(1), 493.913(c)(1),
patient samples to substantiate the Certificate for Provider-Performed 493.915(c)(1), 493.917(c)(1),
instrument or test system’s calibration Microscopy Procedures, and 493.919(c)(1), 493.923(b)(1),
throughout the reportable range for Certificate of Compliance 493.927(c)(1), 493.931(c)(1),
patient test results. 493.933(c)(1), 493.937(c)(1), and
* * * * * § 493.43 [Amended]
493.941(c)(1), remove ‘‘90 percent’’ and
FDA-cleared or approved test system 6. In § 493.43(a), remove the words add, in its place, ‘‘80 percent’’ wherever
means a test system cleared or approved ‘‘tests of moderate complexity it appears.
by the FDA through the premarket (including the subcategory) or high
notification (510(k)) or premarket complexity, or any combination of these § 493.945 [Amended]
approval (PMA) process for in-vitro tests,’’ and add, in their place, the words 17. In § 493.945(a)(1), remove
diagnostic use. Unless otherwise stated, ‘‘nonwaived testing’’. ‘‘§ 493.1257’’ and add, in its place,
‘‘§§ 493.1105(a)(7)(i)(A) and 493.1254 Standard: Maintenance and ensure protection from physical,
493.1274(f)(2)’’. function checks. chemical, biochemical, and electrical
493.1255 Standard: Calibration and hazards, and biohazardous materials.
18. Subpart J, consisting of calibration verification procedures. (e) Records and, as applicable, slides,
§§ 493.1100 through 493.1105, and 493.1256 Standard: Control procedures.
493.1261 Standard: Bacteriology.
blocks, and tissues must be maintained
subpart K, consisting of §§ 493.1200
493.1262 Standard: Mycobacteriology. and stored under conditions that ensure
through 493.1299, are revised to read as
493.1263 Standard: Mycology. proper preservation.
follows:
493.1264 Standard: Parasitology.
Subpart J—Facility Administration for § 493.1103 Standard: Requirements for
493.1265 Standard: Virology.
Nonwaived Testing transfusion services.
493.1267 Standard: Routine chemistry.
Sec. 493.1269 Standard: Hematology. A facility that provides transfusion
493.1100 Condition: Facility 493.1271 Standard: Immunohematology. services must meet all of the
administration. 493.1273 Standard: Histopathology. requirements of this section and
493.1101 Standard: Facilities. 493.1274 Standard: Cytology. document all transfusion-related
493.1103 Standard: Requirements for 493.1276 Standard: Clinical cytogenetics. activities.
transfusion services. 493.1278 Standard: Histocompatibility. (a) Arrangement for services. The
493.1105 Standard: Retention requirements. 493.1281 Standard: Comparison of test
facility must have a transfusion service
results.
Subpart K—Quality Systems for Nonwaived 493.1282 Standard: Corrective actions. agreement reviewed and approved by
Testing 493.1283 Standard: Test records. the responsible party(ies) that govern
493.1200 Introduction. 493.1189 Standard: Analytic systems the procurement, transfer, and
493.1201 Condition: Bacteriology. assessment. availability of blood and blood
493.1202 Condition: Mycobacteriology. products.
Postanalytic Systems
493.1203 Condition: Mycology. (b) Provision of testing. The facility
493.1204 Condition: Parasitology. 493.1290 Condition: Postanalytic systems. must provide prompt ABO grouping,
493.1205 Condition: Virology. 493.1291 Standard: Test report.
D(Rho) typing, unexpected antibody
493.1207 Condition: Syphilis serology. 493.1299 Standard: Postanalytic systems
assessment. detection, compatibility testing, and
493.1208 Condition: General immunology.
laboratory investigation of transfusion
493.1210 Condition: Routine chemistry.
493.1211 Condition: Urinalysis. Subpart J—Facility Administration for reactions on a continuous basis through
493.1212 Condition: Endocrinology. Nonwaived Testing a CLIA-certified laboratory or a
493.1213 Condition: Toxicology. laboratory meeting equivalent
493.1215 Condition: Hematology. § 493.1100 Condition: Facility requirements as determined by CMS.
493.1217 Condition: Immunohematology. administration. (c) Blood and blood products storage
493.1219 Condition: Histopathology. Each laboratory that performs and distribution. (1) If a facility stores
493.1220 Condition: Oral pathology. nonwaived testing must meet the or maintains blood or blood products for
493.1221 Condition: Cytology. applicable requirements under transfusion outside of a monitored
493.1125 Condition: Clinical cytogenetics. §§ 493.1101 through 493.1105, unless refrigerator, the facility must ensure the
493.1226 Condition: Radiobioassay. HHS approves a procedure that provides
493.1227 Condition: Histocompatibility.
storage conditions, including
equivalent quality testing as specified in temperature, are appropriate to prevent
General Laboratory Systems Appendix C of the State Operations deterioration of the blood or blood
493.1230 Condition: General laboratory Manual (CMS Pub. 7). product.
systems. (2) The facility must establish and
493.1231 Standard: Confidentiality of § 493.1101 Standard: Facilities.
follow policies to ensure positive
patient information. (a) The laboratory must be identification of a blood or blood
493.1232 Standard: Specimen identification constructed, arranged, and maintained product recipient.
and integrity. to ensure the following:
493.1233 Standard: Complaint
(d) Investigation of transfusion
(1) The space, ventilation, and reactions. The facility must have
investigations. utilities necessary for conducting all
493.1234 Standard: Communications. procedures for preventing transfusion
phases of the testing process. reactions and when necessary, promptly
493.1235 Standard: Personnel competency
assessment policies. (2) Contamination of patient identify, investigate, and report blood
493.1236 Standard: Evaluation of specimens, equipment, instruments, and blood product transfusion reactions
proficiency testing performance. reagents, materials, and supplies is to the laboratory and, as appropriate, to
493.1239 Standard: General laboratory minimized. Federal and State authorities.
systems assessment. (3) Molecular amplification
Preanalytic Systems procedures that are not contained in § 493.1105 Standard: Retention
closed systems have a uni-directional requirements.
493.1240 Condition: Preanalytic systems.
workflow. This must include separate (a) The laboratory must retain its
493.1241 Standard: Test request.
493.1242 Standard: Specimen submission, areas for specimen preparation, records and, as applicable, slides,
handling, and referral. amplification and product detection, blocks, and tissues as follows:
493.1249 Standard: Preanalytic systems and, as applicable, reagent preparation. (1) Test requisitions and
assessment. (b) The laboratory must have authorizations. Retain records of test
appropriate and sufficient equipment, requisitions and test authorizations,
Analytic Systems
instruments, reagents, materials, and including the patient’s chart or medical
493.1250 Condition: Analytic systems. supplies for the type and volume of record if used as the test requisition or
493.1251 Standard: Procedure manual.
testing it performs. authorization, for at least 2 years.
493.1252 Standard: Test systems,
equipment, instruments, reagents, (c) The laboratory must be in (2) Test procedures. Retain a copy of
materials, and supplies. compliance with applicable Federal, each test procedure for at least 2 years
493.1253 Standard: Establishment and State, and local laboratory requirements. after a procedure has been discontinued.
verification of performance (d) Safety procedures must be Each test procedure must include the
specifications. established, accessible, and observed to dates of initial use and discontinuance.
(3) Analytic systems records. Retain (b) Each of the laboratory’s quality §§ 493.1230 through 493.1256, and
quality control and patient test records systems must include an assessment §§ 93.1281 through 493.1299.
(including instrument printouts, if component that ensures continuous
applicable) and all analytic systems improvement of the laboratory’s § 493.1210 Condition: Routine chemistry.
activities specified in §§ 493.1252 performance and services through If the laboratory provides services in
through 493.1289 for at least 2 years. In ongoing monitoring that identifies, the subspecialty of Routine chemistry,
addition, retain the following: evaluates and resolves problems. the laboratory must meet the
(i) Records of test system performance (c) The various components of the requirements specified in §§ 493.1230
specifications that the laboratory laboratory’s quality systems are used to through 493.1256, § 493.1267, and
establishes or verifies under § 493.1253 meet the requirements in this part and §§ 493.1281 through 493.1299.
for the period of time the laboratory must be appropriate for the specialties § 493.1211 Condition: Urinalysis.
uses the test system but no less than 2 and subspecialties of testing the
years. If the laboratory provides services in
laboratory performs, services it offers,
(ii) Immunohematology records, blood the subspecialty of Urinalysis, the
and clients it serves.
and blood product records, and laboratory must meet the requirements
transfusion records as specified in 21 § 493.1201 Condition: Bacteriology. specified in §§ 493.1230 through
CFR 606.160(b)(3)(ii), (b)(3)(v), and (d). If the laboratory provides services in 493.1256, and §§ 493.1281 through
(4) Proficiency testing records. Retain the subspecialty of Bacteriology, the 493.1299.
all proficiency testing records for at laboratory must meet the requirements
least 2 years. § 493.1212 Condition: Endocrinology.
specified in §§ 493.1230 through If the laboratory provides services in
(5) Laboratory quality systems
493.1256, § 493.1261, and §§ 493.1281 the subspecialty of Endocrinology, the
assessment records. Retain all
through 493.1299. laboratory must meet the requirements
laboratory quality systems assessment
records for at least 2 years. § 493.1202 Condition: Mycobacteriology. specified in §§ 493.1230 through
(6) Test reports. Retain or be able to 493.1256, and §§ 493.1281 through
If the laboratory provides services in
retrieve a copy of the original report 493.1299.
the subspecialty of Mycobacteriology,
(including final, preliminary, and the laboratory must meet the § 493.1213 Condition: Toxicology.
corrected reports) at least 2 years after requirements specified in §§ 493.1230
the date of reporting. In addition, retain If the laboratory provides services in
through 493.1256, § 493.1262, and the subspecialty of Toxicology, the
the following: §§ 493.1281 through 493.1299.
(i) Immunohematology reports as laboratory must meet the requirements
specified in 21 CFR 606.160(b)(3)(ii), § 493.1203 Condition: Mycology. specified in §§ 493.1230 through
(b)(3)(iv), and (d). 493.1256, and §§ 493.1281 through
If the laboratory provides services in 493.1299.
(ii) Pathology test reports for at least
the subspecialty of Mycology, the
10 years after the date of reporting.
(7) Slide, block, and tissue retention— laboratory must meet the requirements § 493.1215 Condition: Hematology.
specified in §§ 493.1230 through If the laboratory provides services in
(i) Slides. 493.1256, § 493.1263, and §§ 493.1281 the specialty of Hematology, the
(A) Retain cytology slide preparations through 493.1299. laboratory must meet the requirements
for at least 5 years from the date of § 493.1204 Condition: Parasitology. specified in §§ 493.1230 through
examination (see § 493.1274(f) for 493.1256, § 493.1269, and §§ 493.1281
proficiency testing exception). If the laboratory provides services in through 493.1299.
(B) Retain histopathology slides for at the subspecialty of Parasitology, the
least 10 years from the date of laboratory must meet the requirements § 493.1217 Condition: Immunohematology.
examination. specified in §§ 493.1230 through If the laboratory provides services in
(ii) Blocks. Retain pathology specimen 493.1256, § 493.1264, and §§ 493.1281 the specialty of Immunohematology, the
blocks for at least 2 years from the date through 493.1299. laboratory must meet the requirements
of examination. specified in §§ 493.1230 through
§ 493.1205 Condition: Virology.
(iii) Tissue. Preserve remnants of 493.1256, § 493.1271, and §§ 493.1281
tissue for pathology examination until a If the laboratory provides services in through 493.1299.
diagnosis is made on the specimen. the subspecialty of Virology, the
(b) If the laboratory ceases operation, laboratory must meet the requirements § 493.1219 Condition: Histopathology.
the laboratory must make provisions to specified in §§ 493.1230 through If the laboratory provides services in
ensure that all records and, as 493.1256, § 493.1265, and §§ 493.1281 the subspecialty of Histopathology, the
applicable, slides, blocks, and tissue are through 493.1299. laboratory must meet the requirements
maintained and available for the time specified in §§ 493.1230 through
§ 493.1207 Condition: Syphilis serology.
frames specified in this section. 493.1256, § 493.1273, and §§ 493.1281
If the laboratory provides services in through 493.1299.
Subpart K—Quality Systems for the subspecialty of Syphilis serology,
Nonwaived Testing the laboratory must meet the § 493.1220 Condition: Oral pathology.
requirements specified in §§ 493.1230 If the laboratory provides services in
§ 493.1200 Introduction. through 493.1256, and §§ 493.1281 the subspecialty of Oral pathology, the
(a) Each laboratory that performs through 493.1299. laboratory must meet the requirements
nonwaived testing must establish and specified in §§ 493.1230 through
maintain written policies and § 493.1208 Condition: General 493.1256, and §§ 493.1281 through
procedures that implement and monitor immunology.
493.1299.
quality systems for all phases of the If the laboratory provides services in
total testing process (that is, preanalytic, the subspecialty of General § 493.1221 Condition: Cytology.
analytic, and postanalytic) as well as immunology, the laboratory must meet If the laboratory provides services in
general laboratory systems. the requirements specified in the subspecialty of Cytology, the
laboratory must meet the requirements § 493.1233 Standard: Complaint assess, and, when indicated, correct
specified in §§ 493.1230 through investigations. problems identified in the general
493.1256, § 493.1274, and §§ 493.1281 The laboratory must have a system in laboratory system requirements
through 493.1299. place to ensure that it documents all specified at §§ 493.1231 through
complaints and problems reported to 493.1236.
§ 493.1225 Condition: Clinical the laboratory. The laboratory must (b) The general laboratory systems
cytogenetics. conduct investigations of complaints, assessment must include a review of the
If the laboratory provides services in when appropriate. effectiveness of corrective actions taken
the specialty of Clinical cytogenetics, to resolve problems, revision of policies
§ 493.1234 Standard: Communications.
the laboratory must meet the and procedures necessary to prevent
The laboratory must have a system in recurrence of problems, and discussion
requirements specified in §§ 493.1230 place to identify and document
through 493.1256, § 493.1276, and of general laboratory systems
problems that occur as a result of a assessment reviews with appropriate
§§ 493.1281 through 493.1299. breakdown in communication between staff.
§ 493.1226 Condition: Radiobioassay. the laboratory and an authorized (c) The laboratory must document all
individual who orders or receives test general laboratory systems assessment
If the laboratory provides services in results. activities.
the specialty of Radiobioassay, the
laboratory must meet the requirements § 493.1235 Standard: Personnel Preanalytic Systems
specified in §§ 493.1230 through competency assessment policies.
As specified in the personnel § 493.1240 Condition: Preanalytic
493.1256, and §§ 493.1281 through
requirements in subpart M, the systems.
493.1299.
laboratory must establish and follow Each laboratory that performs
§ 493.1227 Condition: Histocompatibility. written policies and procedures to nonwaived testing must meet the
assess employee and, if applicable, applicable preanalytic system(s)
If the laboratory provides services in
consultant competency. requirements in §§ 493.1241 and
the specialty of Histocompatibility, the
493.1242, unless HHS approves a
laboratory must meet the requirements § 493.1236 Standard: Evaluation of procedure, specified in Appendix C of
specified in §§ 493.1230 through proficiency testing performance.
the State Operations Manual (CMS Pub.
493.1256, § 493.1278, and §§ 493.1281 (a) The laboratory must review and 7), that provides equivalent quality
through 493.1299. evaluate the results obtained on testing. The laboratory must monitor
proficiency testing performed as and evaluate the overall quality of the
General Laboratory Systems
specified in subpart H of this part. preanalytic systems and correct
§ 493.1230 Condition: General laboratory (b) The laboratory must verify the identified problems as specified in
systems. accuracy of the following: § 493.1249 for each specialty and
(1) Any analyte or subspecialty subspecialty of testing performed.
Each laboratory that performs without analytes listed in subpart I of
nonwaived testing must meet the this part that is not evaluated or scored § 493.1241 Standard: Test request.
applicable general laboratory systems by a CMS-approved proficiency testing (a) The laboratory must have a written
requirements in §§ 493.1231 through program. or electronic request for patient testing
493.1236, unless HHS approves a (2) Any analyte, specialty or from an authorized person.
procedure, specified in Appendix C of subspecialty assigned a proficiency (b) The laboratory may accept oral
the State Operations Manual (CMS Pub. testing score that does not reflect requests for laboratory tests if it solicits
7), that provides equivalent quality laboratory test performance (that is, a written or electronic authorization
testing. The laboratory must monitor when the proficiency testing program within 30 days of the oral request and
and evaluate the overall quality of the does not obtain the agreement required maintains the authorization or
general laboratory systems and correct for scoring as specified in subpart I of documentation of its efforts to obtain
identified problems as specified in this part, or the laboratory receives a the authorization.
§ 493.1239 for each specialty and zero score for nonparticipation, or late (c) The laboratory must ensure the test
subspecialty of testing performed. return of results). requisition solicits the following
(c) At least twice annually, the information:
§ 493.1231 Standard: Confidentiality of laboratory must verify the accuracy of
patient information. (1) The name and address or other
the following: suitable identifiers of the authorized
The laboratory must ensure (1) Any test or procedure it performs
person requesting the test and, if
confidentiality of patient information that is not included in subpart I of this
appropriate, the individual responsible
throughout all phases of the total testing part.
for using the test results, or the name
process that are under the laboratory’s (2) Any test or procedure listed in
and address of the laboratory submitting
control. subpart I of this part for which
the specimen, including, as applicable,
compatible proficiency testing samples
a contact person to enable the reporting
§ 493.1232 Standard: Specimen are not offered by a CMS-approved
of imminently life threatening
identification and integrity. proficiency testing program.
(d) All proficiency testing evaluation laboratory results or panic or alert
The laboratory must establish and and verification activities must be values.
follow written policies and procedures documented. (2) The patient’s name or unique
that ensure positive identification and patient identifier.
optimum integrity of a patient’s § 493.1239 Standard: General laboratory (3) The sex and age or date of birth of
specimen from the time of collection or systems assessment. the patient.
receipt of the specimen through (a) The laboratory must establish and (4) The test(s) to be performed.
completion of testing and reporting of follow written policies and procedures (5) The source of the specimen, when
results. for an ongoing mechanism to monitor, appropriate.
(6) The date and, if appropriate, time to resolve problems, revision of policies (12) Pertinent literature references.
of specimen collection. and procedures necessary to prevent (13) The laboratory’s system for
(7) For Pap smears, the patient’s last recurrence of problems, and discussion entering results in the patient record
menstrual period, and indication of of preanalytic systems assessment and reporting patient results including,
whether the patient had a previous reviews with appropriate staff. when appropriate, the protocol for
abnormal report, treatment, or biopsy. (c) The laboratory must document all reporting imminent life threatening
(8) Any additional information preanalytic systems assessment results, or panic, or alert values.
relevant and necessary for a specific test activities. (14) Description of the course of
to ensure accurate and timely testing action to take if a test system becomes
Analytic Systems inoperable.
and reporting of results, including
interpretation, if applicable. § 493.1250 Condition: Analytic systems. (c) Manufacturer’s test system
(d) The patient’s chart or medical Each laboratory that performs instructions or operator manuals may be
record may be used as the test nonwaived testing must meet the used, when applicable, to meet the
requisition or authorization but must be applicable analytic systems requirements of paragraphs (b)(1)
available to the laboratory at the time of requirements in §§ 493.1251 through through (b)(12) of this section. Any of
testing and available to CMS or a CMS 493.1283, unless HHS approves a the items under paragraphs (b)(1)
agent upon request. procedure, specified in Appendix C of through (b)(12) of this section not
(e) If the laboratory transcribes or the State Operations Manual (CMS Pub. provided by the manufacturer must be
enters test requisition or authorization 7), that provides equivalent quality provided by the laboratory.
information into a record system or a (d) Procedures and changes in
testing. The laboratory must monitor
laboratory information system, the procedures must be approved, signed,
and evaluate the overall quality of the
laboratory must ensure the information and dated by the current laboratory
analytic systems and correct identified
is transcribed or entered accurately. director before use.
problems as specified in § 493.1289 for (e) The laboratory must maintain a
§ 493.1242 Standard: Specimen each specialty and subspecialty of copy of each procedure with the dates
submission, handling, and referral. testing performed. of initial use and discontinuance as
(a) The laboratory must establish and § 493.1251 Standard: Procedure manual. described in § 493.1105(a)(2).
follow written policies and procedures (a) A written procedure manual for all § 493.1252 Standard: Test systems,
for each of the following, if applicable: tests, assays, and examinations equipment, instruments, reagents,
(1) Patient preparation. performed by the laboratory must be materials, and supplies.
(2) Specimen collection. available to, and followed by, laboratory (a) Test systems must be selected by
(3) Specimen labeling, including personnel. Textbooks may supplement the laboratory. The testing must be
patient name or unique patient but not replace the laboratory’s written performed following the manufacturer’s
identifier and, when appropriate, procedures for testing or examining instructions and in a manner that
specimen source. specimens. provides test results within the
(4) Specimen storage and (b) The procedure manual must laboratory’s stated performance
preservation. include the following when applicable specifications for each test system as
(5) Conditions for specimen to the test procedure: determined under § 493.1253.
transportation. (1) Requirements for patient (b) The laboratory must define criteria
(6) Specimen processing. preparation; specimen collection, for those conditions that are essential
(7) Specimen acceptability and labeling, storage, preservation, for proper storage of reagents and
rejection. transportation, processing, and referral; specimens, accurate and reliable test
(8) Specimen referral. and criteria for specimen acceptability system operation, and test result
(b) The laboratory must document the and rejection as described in § 493.1242. reporting. The criteria must be
date and time it receives a specimen. (2) Microscopic examination, consistent with the manufacturer’s
(c) The laboratory must refer a including the detection of inadequately instructions, if provided. These
specimen for testing only to a CLIA- prepared slides. conditions must be monitored and
certified laboratory or a laboratory (3) Step-by-step performance of the documented and, if applicable, include
meeting equivalent requirements as procedure, including test calculations the following:
determined by CMS. and interpretation of results. (1) Water quality.
(d) If the laboratory accepts a referral (4) Preparation of slides, solutions, (2) Temperature.
specimen, written instructions must be calibrators, controls, reagents, stains, (3) Humidity.
available to the laboratory’s clients and and other materials used in testing. (4) Protection of equipment and
must include, as appropriate, the (5) Calibration and calibration instruments from fluctuations and
information specified in paragraphs verification procedures. interruptions in electrical current that
(a)(1) through (a)(7) of this section. (6) The reportable range for test adversely affect patient test results and
results for the test system as established test reports.
§ 493.1249 Standard: Preanalytic systems or verified in § 493.1253.
assessment.
(c) Reagents, solutions, culture media,
(7) Control procedures. control materials, calibration materials,
(a) The laboratory must establish and (8) Corrective action to take when and other supplies, as appropriate, must
follow written policies and procedures calibration or control results fail to meet be labeled to indicate the following:
for an ongoing mechanism to monitor, the laboratory’s criteria for acceptability. (1) Identity and when significant,
assess, and when indicated, correct (9) Limitations in the test titer, strength or concentration.
problems identified in the preanalytic methodology, including interfering (2) Storage requirements.
systems specified at §§ 493.1241 substances. (3) Preparation and expiration dates.
through 493.1242. (10) Reference intervals (normal (4) Other pertinent information
(b) The preanalytic systems values). required for proper use.
assessment must include a review of the (11) Imminently life-threatening test (d) Reagents, solutions, culture media,
effectiveness of corrective actions taken results or panic or alert values. control materials, calibration materials,
and other supplies must not be used specifications verified or established with at least the frequency
when they have exceeded their under paragraph (b)(1) or (b)(2) of this recommended by the manufacturer;
expiration date, have deteriorated, or are section. (2) Using the criteria verified or
of substandard quality. (c) Documentation. The laboratory established by the laboratory as
(e) Components of reagent kits of must document all activities specified specified in § 493.1253(b)(3)—
different lot numbers must not be in this section. (i) Using calibration materials
interchanged unless otherwise specified appropriate for the test system and, if
by the manufacturer. § 493.1254 Standard: Maintenance and possible, traceable to a reference method
function checks.
or reference material of known value;
§ 493.1253 Standard: Establishment and (a) Unmodified manufacturer’s and
verification of performance specifications. equipment, instruments, or test systems. (ii) Including the number, type, and
(a) Applicability. Laboratories are not The laboratory must perform and concentration of calibration materials,
required to verify or establish document the following: as well as acceptable limits for and the
performance specifications for any test (1) Maintenance as defined by the frequency of calibration; and
system used by the laboratory before manufacturer and with at least the (3) Whenever calibration verification
April 24, 2003. frequency specified by the fails to meet the laboratory’s acceptable
(b)(1) Verification of performance manufacturer. limits for calibration verification.
specifications. Each laboratory that (2) Function checks as defined by the (b) Perform and document calibration
introduces an unmodified, FDA-cleared manufacturer and with at least the verification procedures—
or approved test system must do the frequency specified by the (1) Following the manufacturer’s
following before reporting patient test manufacturer. Function checks must be calibration verification instructions;
results: within the manufacturer’s established (2) Using the criteria verified or
(i) Demonstrate that it can obtain limits before patient testing is established by the laboratory under
performance specifications comparable conducted. § 493.1253(b)(3)—
to those established by the manufacturer (b) Equipment, instruments, or test (i) Including the number, type, and
for the following performance systems developed in-house, concentration of the materials, as well
characteristics: commercially available and modified by as acceptable limits for calibration
(A) Accuracy. the laboratory, or maintenance and verification; and
(B) Precision. function check protocols are not (ii) Including at least a minimal (or
(C) Reportable range of test results for provided by the manufacturer. The zero) value, a mid-point value, and a
the test system. laboratory must do the following: maximum value near the upper limit of
(ii) Verify that the manufacturer’s (1)(i) Establish a maintenance the range to verify the laboratory’s
reference intervals (normal values) are protocol that ensures equipment, reportable range of test results for the
appropriate for the laboratory’s patient instrument, and test system test system; and
population. performance that is necessary for (3) At least once every 6 months and
(2) Establishment of performance accurate and reliable test results and test whenever any of the following occur:
specifications. Each laboratory that result reporting. (i) A complete change of reagents for
modifies an FDA-cleared or approved (ii) Perform and document the a procedure is introduced, unless the
test system, or introduces a test system maintenance activities specified in laboratory can demonstrate that
not subject to FDA clearance or paragraph (b)(1)(i) of this section. changing reagent lot numbers does not
approval (including methods developed (2)(i) Define a function check protocol affect the range used to report patient
in-house and standardized methods that ensures equipment, instrument, and test results, and control values are not
such as text book procedures, Gram test system performance that is adversely affected by reagent lot number
stain, or potassium hydroxide necessary for accurate and reliable test changes.
preparations), or uses a test system in results and test result reporting. (ii) There is major preventive
which performance specifications are (ii) Perform and document the maintenance or replacement of critical
not provided by the manufacturer must, function checks, including background parts that may influence test
before reporting patient test results, or baseline checks, specified in performance.
establish for each test system the paragraph (b)(2)(i) of this section. (iii) Control materials reflect an
performance specifications for the Function checks must be within the unusual trend or shift, or are outside of
following performance characteristics, laboratory’s established limits before the laboratory’s acceptable limits, and
as applicable: patient testing is conducted. other means of assessing and correcting
(i) Accuracy. unacceptable control values fail to
(ii) Precision. § 493.1255 Standard: Calibration and identify and correct the problem.
(iii) Analytical sensitivity. calibration verification procedures.
(iv) The laboratory’s established
(iv) Analytical specificity to include Calibration and calibration schedule for verifying the reportable
interfering substances. verification procedures are required to range for patient test results requires
(v) Reportable range of test results for substantiate the continued accuracy of more frequent calibration verification.
the test system. the test system throughout the
(vi) Reference intervals (normal laboratory’s reportable range of test § 493.1256 Standard: Control procedures.
values). results for the test system. Unless (a) For each test system, the laboratory
(vii) Any other performance otherwise specified in this subpart, for is responsible for having control
characteristic required for test each applicable test system the procedures that monitor the accuracy
performance. laboratory must do the following: and precision of the complete analytical
(3) Determination of calibration and (a) Perform and document calibration process.
control procedures. The laboratory must procedures— (b) The laboratory must establish the
determine the test system’s calibration (1) Following the manufacturer’s test number, type, and frequency of testing
procedures and control procedures system instructions, using calibration control materials using, if applicable,
based upon the performance materials provided or specified, and the performance specifications verified
or established by the laboratory as specimens, at least one control material (ii) Check each batch of media for its
specified in § 493.1253(b)(3). containing the substances being ability to support growth and, as
(c) The control procedures must— identified or measured. appropriate, select or inhibit specific
(1) Detect immediate errors that occur (6) Perform control material testing as organisms or produce a biochemical
due to test system failure, adverse specified in this paragraph before response; and
environmental conditions, and operator resuming patient testing when a (iii) Document the physical
performance. complete change of reagents is characteristics of the media when
(2) Monitor over time the accuracy introduced; major preventive compromised and report any
and precision of test performance that maintenance is performed; or any deterioration in the media to the
may be influenced by changes in test critical part that may influence test manufacturer.
system performance and environmental performance is replaced. (5) Follow the manufacturer’s
conditions, and variance in operator (7) Over time, rotate control material specifications for using reagents, media,
performance. testing among all operators who perform and supplies and be responsible for
(d) Unless CMS approves a procedure, the test. results.
specified in Appendix C of the State (8) Test control materials in the same (f) Results of control materials must
Operations Manual (CMS Pub. 7), that manner as patient specimens. meet the laboratory’s and, as applicable,
provides equivalent quality testing, the (9) When using calibration material as the manufacturer’s test system criteria
laboratory must— a control material, use calibration for acceptability before reporting patient
(1) Perform control procedures as material from a different lot number test results.
defined in this section unless otherwise than that used to establish a cut-off (g) The laboratory must document all
specified in the additional specialty and value or to calibrate the test system. control procedures performed.
subspecialty requirements at (10) Establish or verify the criteria for (h) If control materials are not
§§ 493.1261 through 493.1278. acceptability of all control materials. available, the laboratory must have an
(2) For each test system, perform (i) When control materials providing alternative mechanism to detect
control procedures using the number quantitative results are used, statistical immediate errors and monitor test
and frequency specified by the parameters (for example, mean and system performance over time. The
manufacturer or established by the standard deviation) for each batch and performance of alternative control
laboratory when they meet or exceed the lot number of control materials must be procedures must be documented.
requirements in paragraph (d)(3) of this defined and available. § 493.1261 Standard: Bacteriology.
section. (ii) The laboratory may use the stated
value of a commercially assayed control (a) The laboratory must check the
(3) At least once each day patient
material provided the stated value is for following for positive and negative
specimens are assayed or examined
the methodology and instrumentation reactivity using control organisms:
perform the following for— (1) Each day of use for beta-lactamase
(i) Each quantitative procedure, employed by the laboratory and is
methods other than CefinaseTM.
include two control materials of verified by the laboratory. (2) Each week of use for Gram stains.
different concentrations; (iii) Statistical parameters for (3) When each batch (prepared in-
(ii) Each qualitative procedure, unassayed control materials must be house), lot number (commercially
include a negative and positive control established over time by the laboratory prepared), and shipment of antisera is
material; through concurrent testing of control prepared or opened, and once every 6
(iii) Test procedures producing graded materials having previously determined months thereafter.
or titered results, include a negative statistical parameters. (b) For antimicrobial susceptibility
control material and a control material (e) For reagent, media, and supply tests, the laboratory must check each
with graded or titered reactivity, checks, the laboratory must do the batch of media and each lot number and
respectively; following: shipment of antimicrobial agent(s)
(iv) Each test system that has an (1) Check each batch (prepared in- before, or concurrent with, initial use,
extraction phase, include two control house), lot number (commercially using approved control organisms.
materials, including one that is capable prepared) and shipment of reagents, (1) Each day tests are performed, the
of detecting errors in the extraction disks, stains, antisera, and identification laboratory must use the appropriate
process; and systems (systems using two or more control organism(s) to check the
(v) Each molecular amplification substrates or two or more reagents, or a procedure.
procedure, include two control combination) when prepared or opened (2) The laboratory’s zone sizes or
materials and, if reaction inhibition is a for positive and negative reactivity, as minimum inhibitory concentration for
significant source of false negative well as graded reactivity, if applicable. control organisms must be within
results, a control material capable of (2) Each day of use (unless otherwise established limits before reporting
detecting the inhibition. specified in this subpart), test staining patient results.
(4) For thin layer chromatography— materials for intended reactivity to (c) The laboratory must document all
(i) Spot each plate or card, as ensure predictable staining control procedures performed, as
applicable, with a calibrator containing characteristics. Control materials for specified in this section.
all known substances or drug groups, as both positive and negative reactivity
appropriate, which are identified by must be included, as appropriate. § 493.1262 Standard: Mycobacteriology.
thin layer chromatography and reported (3) Check fluorescent and (a) Each day of use, the laboratory
by the laboratory; and immunohistochemical stains for must check all reagents or test
(ii) Include at least one control positive and negative reactivity each procedures used for mycobacteria
material on each plate or card, as time of use. identification with at least one acid-fast
applicable, which must be processed (4) Before, or concurrent with the organism that produces a positive
through each step of patient testing, initial use— reaction and an acid-fast organism that
including extraction processes. (i) Check each batch of media for produces a negative reaction.
(5) For each electrophoretic procedure sterility if sterility is required for (b) For antimycobacterial
include, concurrent with patient testing; susceptibility tests, the laboratory must
check each batch of media and each lot (b) The laboratory must document all products. Blood and blood product
number and shipment of control procedures performed, as testing and distribution must comply
antimycobacterial agent(s) before, or specified in this section. with 21 CFR 606.100(b)(12);
concurrent with, initial use, using an 606.160(b)(3)(ii) and (b)(3)(v); 610.40;
appropriate control organism(s). § 493.1267 Standard: Routine chemistry. 640.5(a), (b), (c), and (e); and 640.11(b).
(1) The laboratory must establish For blood gas analyses, the laboratory (c) Blood and blood products storage.
limits for acceptable control results. must perform the following: Blood and blood products must be
(2) Each week tests are performed, the (a) Calibrate or verify calibration stored under appropriate conditions that
laboratory must use the appropriate according to the manufacturer’s include an adequate temperature alarm
control organism(s) to check the specifications and with at least the system that is regularly inspected.
procedure. frequency recommended by the (1) An audible alarm system must
(3) The results for the control manufacturer. monitor proper blood and blood product
organism(s) must be within established (b) Test one sample of control
storage temperature over a 24-hour
limits before reporting patient results. material each 8 hours of testing using a
period.
(c) The laboratory must document all combination of control materials that
include both low and high values on (2) Inspections of the alarm system
control procedures performed, as
each day of testing. must be documented.
specified in this section.
(c) Test one sample of control material (d) Retention of samples of transfused
§ 493.1263 Standard: Mycology. each time specimens are tested unless blood. According to the laboratory’s
(a) The laboratory must check each automated instrumentation internally established procedures, samples of each
batch (prepared in-house), lot number verifies calibration at least every 30 unit of transfused blood must be
(commercially prepared), and shipment minutes. retained for further testing in the event
of lactophenol cotton blue when (d) Document all control procedures of transfusion reactions. The laboratory
prepared or opened for intended performed, as specified in this section. must promptly dispose of blood not
reactivity with a control organism(s). retained for further testing that has
(b) For antifungal susceptibility tests, § 493.1269 Standard: Hematology. passed its expiration date.
the laboratory must check each batch of (a) For manual cell counts performed (e) Investigation of transfusion
media and each lot number and using a hemocytometer— reactions. (1) According to its
shipment of antifungal agent(s) before, (1) One control material must be established procedures, the laboratory
or concurrent with, initial use, using an tested each 8 hours of operation; and that performs compatibility testing, or
appropriate control organism(s). (2) Patient specimens and control issues blood or blood products, must
(1) The laboratory must establish materials must be tested in duplicate. promptly investigate all transfusion
limits for acceptable control results. (b) For all nonmanual coagulation test reactions occurring in facilities for
(2) Each day tests are performed, the systems, the laboratory must include which it has investigational
laboratory must use the appropriate two levels of control material each 8 responsibility and make
control organism(s) to check the hours of operation and each time a recommendations to the medical staff
procedure. reagent is changed. regarding improvements in transfusion
(3) The results for the control (c) For manual coagulation tests— procedures.
organism(s) must be within established (1) Each individual performing tests
(2) The laboratory must document, as
limits before reporting patient results. must test two levels of control materials
applicable, that all necessary remedial
(c) The laboratory must document all before testing patient samples and each
actions are taken to prevent recurrences
control procedures performed, as time a reagent is changed; and
of transfusion reactions and that all
specified in this section. (2) Patient specimens and control
policies and procedures are reviewed to
materials must be tested in duplicate.
§ 493.1264 Standard: Parasitology. (d) The laboratory must document all assure they are adequate to ensure the
(a) The laboratory must have available control procedures performed, as safety of individuals being transfused.
a reference collection of slides or specified in this section. (f) The laboratory must document all
photographs and, if available, gross control procedures performed, as
specimens for identification of parasites § 493.1271 Standard: Immunohematology. specified in this section.
and use these references in the (a) Patient testing. (1) The laboratory
§ 493.1273 Standard: Histopathology.
laboratory for appropriate comparison must perform ABO grouping, D(Rho)
typing, unexpected antibody detection, (a) Fluorescent and
with diagnostic specimens. immunohistochemical stains must be
(b) The laboratory must calibrate and antibody identification, and
compatibility testing by following the checked for positive and negative
use the calibrated ocular micrometer for
manufacturer’s instructions, if provided, reactivity each time of use. For all other
determining the size of ova and
and as applicable, 21 CFR 606.151(a) differential or special stains, a control
parasites, if size is a critical parameter.
(c) Each month of use, the laboratory through (e). slide of known reactivity must be
must check permanent stains using a (2) The laboratory must determine stained with each patient slide or group
fecal sample control material that will ABO group by concurrently testing of patient slides. Reaction(s) of the
demonstrate staining characteristics. unknown red cells with, at a minimum, control slide with each special stain
(d) The laboratory must document all anti-A and anti-B grouping reagents. For must be documented.
control procedures performed, as confirmation of ABO group, the (b) The laboratory must retain stained
specified in this section. unknown serum must be tested with slides, specimen blocks, and tissue
known A1 and B red cells. remnants as specified in § 493.1105. The
§ 493.1265 Standard: Virology. (3) The laboratory must determine the remnants of tissue specimens must be
(a) When using cell culture to isolate D(Rho) type by testing unknown red maintained in a manner that ensures
or identify viruses, the laboratory must cells with anti-D (anti-Rho) blood typing proper preservation of the tissue
simultaneously incubate a cell substrate reagent. specimens until the portions submitted
control or uninoculated cells as a (b) Immunohematological testing and for microscopic examination have been
negative control material. distribution of blood and blood examined and a diagnosis made by an
individual qualified under (B) A cytology general supervisor deviation and, if appropriate, corrective
§§ 493.1449(b), (l), or (m). qualified under § 493.1469. actions taken.
(c) An individual who has (C) A cytotechnologist qualified under (d) Workload limits. The laboratory
successfully completed a training § 493.1483 who has the experience must establish and follow written
program in neuromuscular pathology specified in § 493.1469(b)(2). policies and procedures that ensure the
approved by HHS may examine and (ii) Cases must be randomly selected following:
provide reports for neuromuscular from the total caseload and include (1) The technical supervisor
pathology. negatives and those from patients or establishes a maximum workload limit
(d) Tissue pathology reports must be groups of patients that are identified as for each individual who performs
signed by an individual qualified as having a higher than average probability primary screening.
specified in paragraph (b) or, as of developing cervical cancer based on (i) The workload limit is based on the
appropriate, paragraph (c) of this available patient information. individual’s performance using
section. If a computer report is (iii) The review of those cases selected evaluations of the following:
generated with an electronic signature, must be completed before reporting (A) Review of 10 percent of the cases
it must be authorized by the individual patient results. interpreted as negative for the
who performed the examination and (2) Laboratory comparison of clinical conditions defined in paragraph (e)(1) of
made the diagnosis. information, when available, with this section.
(e) The laboratory must use acceptable cytology reports and comparison of all (B) Comparison of the individual’s
terminology of a recognized system of gynecologic cytology reports with a interpretation with the technical
disease nomenclature in reporting diagnosis of high-grade squamous supervisor’s confirmation of patient
results. intraepithelial lesion (HSIL), smears specified in paragraphs (e)(1)
(f) The laboratory must document all adenocarcinoma, or other malignant and (e)(3) of this section.
control procedures performed, as neoplasms with the histopathology (ii) Each individual’s workload limit
specified in this section. report, if available in the laboratory is reassessed at least every 6 months and
(either on-site or in storage), and adjusted when necessary.
§ 493.1274 Standard: Cytology. (2) The maximum number of slides
determination of the causes of any
(a) Cytology slide examination site. examined by an individual in each 24-
discrepancies.
All cytology slide preparations must be hour period does not exceed 100 slides
(3) For each patient with a current
evaluated on the premises of a (one patient specimen per slide;
HSIL, adenocarcinoma, or other
laboratory certified to conduct testing in gynecologic, nongynecologic, or both)
malignant neoplasm, laboratory review
the subspecialty of cytology. irrespective of the site or laboratory.
(b) Staining. The laboratory must have of all normal or negative gynecologic
specimens received within the previous This limit represents an absolute
available and follow written policies maximum number of slides and must
and procedures for each of the 5 years, if available in the laboratory
(either on-site or in storage). If not be employed as an individual’s
following, if applicable: performance target. In addition—
(1) All gynecologic slide preparations significant discrepancies are found that
will affect current patient care, the (i) The maximum number of 100
must be stained using a Papanicolaou or slides is examined in no less than an 8-
modified Papanicolaou staining method. laboratory must notify the patient’s
physician and issue an amended report. hour workday;
(2) Effective measures to prevent (ii) For the purposes of establishing
cross-contamination between (4) Records of initial examinations
and all rescreening results must be workload limits for individuals
gynecologic and nongynecologic examining slides in less than an 8-hour
specimens during the staining process documented.
(5) An annual statistical laboratory workday (includes full-time employees
must be used. with duties other than slide
(3) Nongynecologic specimens that evaluation of the number of—
(i) Cytology cases examined; examination and part-time employees),
have a high potential for cross- a period of 8 hours is used to prorate the
contamination must be stained (ii) Specimens processed by specimen
type; number of slides that may be examined.
separately from other nongynecologic The formula—
specimens, and the stains must be (iii) Patient cases reported by
filtered or changed following staining. diagnosis (including the number Number of hours examining slides × 100
(c) Control procedures. The laboratory reported as unsatisfactory for diagnostic
must establish and follow written interpretation); 8
policies and procedures for a program (iv) Gynecologic cases with a is used to determine maximum slide
designed to detect errors in the diagnosis of HSIL, adenocarcinoma, or volume to be examined;
performance of cytologic examinations other malignant neoplasm for which (iii) Nongynecologic slide preparation
and the reporting of results. The histology results were available for made using liquid-based slide
program must include the following: comparison; preparatory techniques that result in
(1) A review of slides from at least 10 (v) Gynecologic cases where cytology cell dispersion over one-half or less of
percent of the gynecologic cases and histology are discrepant; and the total available slide may be counted
interpreted by individuals qualified (vi) Gynecologic cases where any as one-half slide; and
under §§ 493.1469 or 493.1483, to be rescreen of a normal or negative (iv) Technical supervisors who
negative for epithelial cell abnormalities specimen results in reclassification as perform primary screening are not
and other malignant neoplasms (as low-grade squamous intraepithelial required to include tissue pathology
defined in paragraph (e)(1) of this lesion (LSIL), HSIL, adenocarcinoma, or slides and previously examined
section). other malignant neoplasms. cytology slides (gynecologic and
(i) The review must be performed by (6) An evaluation of the case reviews nongynecologic) in the 100 slide
an individual who meets one of the of each individual examining slides workload limit.
following qualifications: against the laboratory’s overall (3) The laboratory must maintain
(A) A technical supervisor qualified statistical values, documentation of any records of the total number of slides
under §§ 493.1449(b) or (k). discrepancies, including reasons for the examined by each individual during
ER24JA03.000</GPH>
each 24-hour period and the number of (2) Slides may be loaned to of specimens (donor and recipient) and
hours spent examining slides in the 24- proficiency testing programs in lieu of reagents. The laboratory must have an
hour period irrespective of the site or maintaining them for the required time emergency plan for alternate storage.
laboratory. period, provided the laboratory receives (2) All patient specimens must be
(4) Records are available to document written acknowledgment of the receipt easily retrievable.
the workload limit for each individual. of slides by the proficiency testing (3) Reagent typing sera inventory
(e) Slide examination and reporting. program and maintains the prepared in-house must indicate source,
The laboratory must establish and acknowledgment to document the loan bleeding date and identification
follow written policies and procedures of these slides. number, reagent specificity, and volume
that ensure the following: (3) Documentation of slides loaned or remaining.
(1) A technical supervisor confirms referred for purposes other than (4) If the laboratory uses immunologic
each gynecologic slide preparation proficiency testing must be maintained. reagents (for example, antibodies,
interpreted to exhibit reactive or (4) All slides must be retrievable upon antibody-coated particles, or
reparative changes or any of the request. complement) to facilitate or enhance the
following epithelial cell abnormalities: (g) Automated and semi-automated isolation of lymphocytes, or lymphocyte
(i) Squamous cell. screening devices. When performing subsets, the efficacy of the methods
(A) Atypical squamous cells of evaluations using automated and semi- must be monitored with appropriate
undetermined significance (ASC–US) or automated screening devices, the quality control procedures.
cannot exclude HSIL (ASC–H). laboratory must follow manufacturer’s (5) Participate in at least one national
(B) LSIL-Human papillomavirus or regional cell exchange program, if
instructions for preanalytic, analytic,
(HPV)/mild dysplasia/cervical available, or develop an exchange
and postanalytic phases of testing, as
intraepithelial neoplasia 1 (CIN 1). system with another laboratory in order
(C) HSIL-moderate and severe applicable, and meet the applicable
requirements of this subpart K. to validate interlaboratory
dysplasia, carcinoma in situ (CIS)/CIN 2
(h) The laboratory must document all reproducibility.
and CIN 3 or with features suspicious
control procedures performed, as (b) HLA typing. The laboratory must
for invasion.
(D) Squamous cell carcinoma. specified in this section. do the following:
(ii) Glandular cell. (1) Use a technique(s) that is
§ 493.1276 Standard: Clinical established to optimally define, as
(A) Atypical cells not otherwise cytogenetics.
specified (NOS) or specified in applicable, HLA Class I and II
comments (endocervical, endometrial, (a) The laboratory must have policies specificities.
or glandular). and procedures for ensuring accurate (2) HLA type all potential transplant
(B) Atypical cells favor neoplastic and reliable patient specimen recipients at a level appropriate to
(endocervical or glandular). identification during the process of support clinical transplant protocol and
(C) Endocervical adenocarcinoma in accessioning, cell preparation, donor selection.
situ. photographing or other image (3) HLA type cells from organ donors
(D) Adenocarcinoma endocervical, reproduction technique, photographic referred to the laboratory.
adenocarcinoma endometrial, printing, and reporting and storage of (4) Use HLA antigen terminology that
adenocarcinoma extrauterine, and results, karyotypes, and photographs. conforms to the latest report of the
adenocarcinoma NOS. (b) The laboratory must have records World Health Organization (W.H.O.)
(iii) Other malignant neoplasms. that document the following: Committee on Nomenclature. Potential
(2) The report of gynecologic slide (1) The media used, reactions new antigens not yet approved by this
preparations with conditions specified observed, number of cells counted, committee must have a designation that
in paragraph (e)(1) of this section must number of cells karyotyped, number of cannot be confused with W.H.O.
be signed to reflect the technical chromosomes counted for each terminology.
supervisory review or, if a computer metaphase spread, and the quality of the (5) Have available and follow written
report is generated with signature, it banding. criteria for the following:
must reflect an electronic signature (2) The resolution is appropriate for (i) The preparation of cells or cellular
authorized by the technical supervisor the type of tissue or specimen and the extracts (for example, solubilized
who performed the review. type of study required based on the antigens and nucleic acids), as
(3) All nongynecologic preparations clinical information provided to the applicable to the HLA typing
are reviewed by a technical supervisor. laboratory. technique(s) performed.
The report must be signed to reflect (3) An adequate number of karyotypes (ii) Selecting typing reagents, whether
technical supervisory review or, if a are prepared for each patient. prepared in-house or commercially.
computer report is generated with (c) Determination of sex must be (iii) Ensuring that reagents used for
signature, it must reflect an electronic performed by full chromosome analysis. typing are adequate to define all HLA–
signature authorized by the technical (d) The laboratory report must include A, B and DR specificities that are
supervisor who performed the review. a summary and interpretation of the officially recognized by the most recent
(4) Unsatisfactory specimens or slide observations, number of cells counted W.H.O. Committee on Nomenclature
preparations are identified and reported and analyzed, and use the International and for which reagents are readily
as unsatisfactory. System of Cytogenetic Nomenclature. available.
(5) The report contains narrative (e) The laboratory must document all (iv) The assignment of HLA antigens.
descriptive nomenclature for all results. control procedures performed, as (v) When antigen redefinition and
(6) Corrected reports issued by the specified in this section. retyping are required.
laboratory indicate the basis for (6) Check each HLA typing by testing,
correction. § 493.1278 Standard: Histocompatibility. at a minimum the following:
(f) Record and slide retention. (1) The (a) General. The laboratory must meet (i) A positive control material.
laboratory must retain all records and the following requirements: (ii) A negative control material in
slide preparations as specified in (1) An audible alarm system must be which, if applicable to the technique
§ 493.1105. used to monitor the storage temperature performed, cell viability at the end of
incubation is sufficient to permit solubilized antigens and nucleic acids), (1) Patient age.
accurate interpretation of results. In as applicable to the crossmatch (2) Sex.
assays in which cell viability is not technique(s) performed. (3) Diagnosis or pertinent clinical
required, the negative control result (3) Check each crossmatch and data.
must be sufficiently different from the compatibility test for HLA Class II (4) Distribution of patient test results.
positive control result to permit antigenic differences using control (5) Relationship with other test
accurate interpretation of results. materials to monitor the test parameters.
(iii) Positive control materials for components and each phase of the test (c) The laboratory must document all
specific cell types when applicable (that system to ensure acceptable test result comparison activities.
is, T cells, B cells, and monocytes). performance.
§ 493.1282 Standard: Corrective actions.
(c) Disease-associated studies. The (f) Transplantation. Laboratories
laboratory must check each typing for performing histocompatibility testing (a) Corrective action policies and
disease-associated HLA antigens using for transfusion and transplantation procedures must be available and
control materials to monitor the test purposes must do the following: followed as necessary to maintain the
components and each phase of the test (1) Have available and follow written laboratory’s operation for testing patient
system to ensure acceptable policies and protocols specifying the specimens in a manner that ensures
performance. histocompatibility testing (that is, HLA accurate and reliable patient test results
(d) Antibody Screening. The typing, antibody screening, and reports.
laboratory must do the following: compatibility testing and (b) The laboratory must document all
(1) Use a technique(s) that detects crossmatching) to be performed for each corrective actions taken, including
HLA-specific antibody with a specificity type of cell, tissue or organ to be actions taken when any of the following
equivalent or superior to that of the transfused or transplanted. The occur:
basic complement-dependent laboratory’s policies must include, as (1) Test systems do not meet the
microlymphocytotoxicity assay. applicable— laboratory’s verified or established
(2) Use a method that distinguishes (i) Testing protocols for cadaver performance specifications, as
antibodies to HLA Class II antigens from donor, living, living-related, and determined in § 493.1253(b), which
antibodies to Class I antigens to detect combined organ and tissue transplants; include but are not limited to—
antibodies to HLA Class II antigens. (ii) Testing protocols for patients at (i) Equipment or methodologies that
(3) Use a panel that contains all the high risk for allograft rejection; and perform outside of established operating
major HLA specificities and common (iIi) The level of testing required to parameters or performance
splits. If the laboratory does not use support clinical transplant protocols (for specifications;
commercial panels, it must maintain a example, antigen or allele level). (ii) Patient test values that are outside
list of individuals for fresh panel (2) For renal allotransplantation and of the laboratory’s reportable range of
bleeding. combined organ and tissue transplants test results for the test system; and
(4) Make a reasonable attempt to have in which a kidney is to be transplanted, (iii) When the laboratory determines
available monthly serum specimens for have available results of final that the reference intervals (normal
all potential transplant recipients for crossmatches before the kidney is values) for a test procedure are
periodic antibody screening and transplanted. inappropriate for the laboratory’s
crossmatch. (3) For nonrenal transplantation, if patient population.
(5) Have available and follow a HLA testing and final crossmatches (2) Results of control or calibration
written policy consistent with clinical were not performed prospectively materials, or both, fail to meet the
transplant protocols for the frequency of because of an emergency situation, the laboratory’s established criteria for
screening potential transplant recipient laboratory must document the acceptability. All patient test results
sera for preformed HLA-specific circumstances, if known, under which obtained in the unacceptable test run
antibodies. the emergency transplant was and since the last acceptable test run
(6) Check each antibody screening by performed, and records of the transplant must be evaluated to determine if
testing, at a minimum the following: must reflect any information provided patient test results have been adversely
(i) A positive control material to the laboratory by the patient’s affected. The laboratory must take the
containing antibodies of the appropriate physician. corrective action necessary to ensure the
isotype for the assay. (g) The laboratory must document all reporting of accurate and reliable
(ii) A negative control material. control procedures performed, as patient test results.
(7) As applicable, have available and specified in this section. (3) The criteria for proper storage of
follow written criteria and procedures reagents and specimens, as specified
for antibody identification to the level § 493.1281 Standard: Comparison of test under § 493.1252(b), are not met.
appropriate to support clinical results.
transplant protocol. (a) If a laboratory performs the same § 493.1283 Standard: Test records.
(e) Crossmatching. The laboratory test using different methodologies or (a) The laboratory must maintain an
must do the following: instruments, or performs the same test information or record system that
(1) Use a technique(s) documented to at multiple testing sites, the laboratory includes the following:
have increased sensitivity in must have a system that twice a year (1) The positive identification of the
comparison with the basic complement- evaluates and defines the relationship specimen.
dependent microlymphocytotoxicity between test results using the different (2) The date and time of specimen
assay. methodologies, instruments, or testing receipt into the laboratory.
(2) Have available and follow written sites. (3) The condition and disposition of
criteria for the following: (b) The laboratory must have a system specimens that do not meet the
(i) Selecting appropriate patient to identify and assess patient test results laboratory’s criteria for specimen
serum samples for crossmatching. that appear inconsistent with the acceptability.
(ii) The preparation of donor cells or following relevant criteria, when (4) The records and dates of all
cellular extracts (for example, available: specimen testing, including the identity
of the personnel who performed the available to the laboratory and to CMS (2) The referring laboratory may
test(s). or a CMS agent upon request. permit each testing laboratory to send
(b) Records of patient testing (c) The test report must indicate the the test result directly to the authorized
including, if applicable, instrument following: person who initially requested the test.
printouts, must be retained. (1) For positive patient identification, The referring laboratory must retain or
either the patient’s name and be able to produce an exact duplicate of
§ 493.1289 Standard: Analytic systems identification number, or an unique each testing laboratory’s report; and
assessment. patient identifier and identification (3) The authorized person who orders
(a) The laboratory must establish and number. a test must be notified by the referring
follow written policies and procedures (2) The name and address of the laboratory of the name and address of
for an ongoing mechanism to monitor, laboratory location where the test was each laboratory location where the test
assess, and when indicated, correct performed. was performed.
problems identified in the analytic (3) The test report date. (j) All test reports or records of the
systems specified in §§ 493.1251 (4) The test performed. information on the test reports must be
through 493.1283. (5) Specimen source, when maintained by the laboratory in a
(b) The analytic systems assessment appropriate. manner that permits ready identification
must include a review of the (6) The test result and, if applicable, and timely accessibility.
effectiveness of corrective actions taken the units of measurement or (k) When errors in the reported
to resolve problems, revision of policies interpretation, or both. patient test results are detected, the
and procedures necessary to prevent (7) Any information regarding the laboratory must do the following:
recurrence of problems, and discussion condition and disposition of specimens (1) Promptly notify the authorized
of analytic systems assessment reviews that do not meet the laboratory’s criteria person ordering the test and, if
with appropriate staff. for acceptability. applicable, the individual using the test
(c) The laboratory must document all (d) Pertinent ‘‘reference intervals’’ or results of reporting errors.
analytic systems assessment activities. ‘‘normal’’ values, as determined by the (2) Issue corrected reports promptly to
laboratory performing the tests, must be the authorized person ordering the test
Postanalytic Systems available to the authorized person who and, if applicable, the individual using
ordered the tests and, if applicable, the the test results.
§ 493.1290 Condition: Postanalytic
systems.
individual responsible for using the test (3) Maintain duplicates of the original
results. report, as well as the corrected report.
Each laboratory that performs (e) The laboratory must, upon request,
nonwaived testing must meet the make available to clients a list of test § 493.1299 Standard: Postanalytic systems
applicable postanalytic systems methods employed by the laboratory assessment.
requirements in § 493.1291 unless HHS and, as applicable, the performance (a) The laboratory must establish and
approves a procedure, specified in specifications established or verified as follow written policies and procedures
Appendix C of the State Operations specified in § 493.1253. In addition, for an ongoing mechanism to monitor,
Manual (CMS Pub. 7) that provides information that may affect the assess and, when indicated, correct
equivalent quality testing. The interpretation of test results, for problems identified in the postanalytic
laboratory must monitor and evaluate example test interferences, must be systems specified in § 493.1291.
the overall quality of the postanalytic provided upon request. Pertinent (b) The postanalytic systems
systems and correct identified problems updates on testing information must be assessment must include a review of the
as specified in § 493.1299 for each provided to clients whenever changes effectiveness of corrective actions taken
specialty and subspecialty of testing occur that affect the test results or to resolve problems, revision of policies
performed. interpretation of test results. and procedures necessary to prevent
§ 493.1291 Standard: Test report. (f) Test results must be released only recurrence of problems, and discussion
to authorized persons and, if applicable, of postanalytic systems assessment
(a) The laboratory must have adequate the individual responsible for using the reviews with appropriate staff.
manual or electronic systems in place to test results and the laboratory that (c) The laboratory must document all
ensure test results and other patient- initially requested the test. postanalytic systems assessment
specific data are accurately and reliably (g) The laboratory must immediately activities.
sent from the point of data entry alert the individual or entity requesting
(whether interfaced or entered the test and, if applicable, the Subpart M—Personnel for Nonwaived
manually) to final report destination, in individual responsible for using the test Testing
a timely manner. This includes the results when any test result indicates an
following: imminent life-threatening condition, or 19. Revise the heading of Subpart M
(1) Results reported from calculated panic or alert values. to read as set forth above.
data. (h) When the laboratory cannot report § 493.1359 [Amended]
(2) Results and patient-specific data patient test results within its established
electronically reported to network or time frames, the laboratory must 20. § 493.1359(b)(2), remove the
interfaced systems. determine, based on the urgency of the reference to ‘‘subpart P’’.
(3) Manually transcribed or patient test(s) requested, the need to § 493.1407 [Amended]
electronically transmitted results and notify the appropriate individual(s) of
patient-specific information reported the delayed testing. 21. In § 493.1407(e)(5), remove the
directly or upon receipt from outside (i) If a laboratory refers patient word ‘‘assurance’’ and, add in its place,
referral laboratories, satellite or point-of- specimens for testing— the word ‘‘assessment’’.
care testing locations. (1) The referring laboratory must not 22. In § 493.1443, paragraph (b)
(b) Test report information revise results or information directly introductory text is republished, and
maintained as part of the patient’s chart related to the interpretation of results paragraph (b)(3) is revised to read as
or medical record must be readily provided by the testing laboratory; follows:
§ 493.1443 Standard: Laboratory director § 493.1451 [Amended] a. In paragraph (e)(1), remove the
qualifications. words ‘‘tests and examinations of
24. In § 493.1451(c)(4), remove the
* * * * * cross reference to ‘‘§ 493.1257(c)’’ and moderate complexity (including the
(b) The laboratory director must— add, in its place, ‘‘§ 493.1274(d) and subcategory) and high complexity’’ and
* * * * * (e)’’. add, in their place, the words
(3) Hold an earned doctoral degree in ‘‘nonwaived testing’’.
a chemical, physical, biological, or § 493.1471 and § 493.1485 [Amended]
clinical laboratory science from an b. Revise paragraph (e)(4) to read as
25. In §§ 493.1471(b)(2) and follows:
accredited institution and— 493.1485(a), remove the cross reference
(i) Be certified and continue to be * * * * *
to ‘‘§ 493.1257(d)’’ and add, in its place,
certified by a board approved by HHS; (e) * * *
‘‘§ 493.1274(c)’’.
or
(ii) Before February 24, 2003, must (4) Facility administration and quality
Subpart P—[Reserved] systems standards.
have served or be serving as a director
of a laboratory performing high 26. Subpart P consisting of * * * * *
complexity testing and must have at §§ 493.1701 through 493.1721, is Dated: October 7, 2002.
least— removed and reserved.
(A) Two years of laboratory training or Thomas A. Scully,
experience, or both; and Subpart R—Enforcement Procedures Administrator, Centers for Medicare &
(B) Two years of laboratory Medicaid Services.
experience directing or supervising high § 493.1844 [Amended]
Dated: December 13, 2002.
complexity testing. 27. In § 493.1844(c)(1), remove the Tommy G. Thompson,
* * * * * reference to ‘‘subpart P’’.
Secretary.
§ 493.1445 [Amended] Subpart T—Consultations [FR Doc. 03–1230 Filed 1–23–03; 8:45 am]
23. In § 493.1445(e)(5), remove the BILLING CODE 4120–01–P
§ 493.2001 [Amended]
word ‘‘assurance’’ and add, in its place,
the word ‘‘assessment’’. 28. Amend § 493.2001 as follows:

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42 CFR Part 493

Patient test management; moderate complexity

§ 493.1109(g) .............................................. Test report ........................................................ § 493.1291(e)

§ 493.1205(c)(1)(iv) ..................................... Test systems, equipment, instruments, re- § 493.1252(b)(4)

§ 493.1213(b)(2)(ii) ...................................... Establishment and verification of performance § 493.1253(b)(3)

§ 493.1218(b)(3)(i) ....................................... Control procedures .......................................... § 493.1256(d)(5)

§ 493.1229(a) .............................................. Mycobacteriology ............................................. § 493.1262(a)

§ 493.1257(a) .............................................. Cytology ........................................................... § 493.1274(b)

§ 493.1265(a)(6)(ii) ...................................... Histocompatibility ............................................. § 493.1278(b)(3)

Quality assurance for Moderate Complexity (in-

Labs affected Savings (costs) † Labs affected Savings (costs) †

Method Verification ........................................ 11,248 ($11.3–20.1) ..................... 29,601 ($49.6–88.0)

TABLE 2.—IMPACTS DUE TO REGULATORY CHANGES: ANNUAL IMPACTS OVER 5 YEARS

Year 1 Year 2 Year 3 Year 4 Year 5 5-Year total

Less QC for Other

TABLE 2.—IMPACTS DUE TO REGULATORY CHANGES: ANNUAL IMPACTS OVER 5 YEARS—Continued

Year 1 Year 2 Year 3 Year 4 Year 5 5-Year total

TABLE 3.—CERTIFICATE TYPE BY LABORATORY TYPE

Compliance Waiver Accreditation PPM State

Hospital .................................................. 1,392 15 1,231 14 5,475 62 224 3 498 6 8,820

TABLE 4.—CHANGES IN CERTIFICATE TYPE, 1998 TO 2001

Compliance .............................................................................................. 28,324 17 27,819 16 25,145 15 22,720 13

Hospital 1,392 354 254,310 444 32 56 4 148 11 744 53

TABLE 6.—IMPACT OF METHOD VERIFICATION, NEW SINGLE TESTS

TABLE 7.—IMPACT OF METHOD VERIFICATION, ANALYZER REPLACEMENT

TDM ................. 3,230 646 $46.3–185.0 $21.6 $67.9–206.6 $0.45–0.56 $0.51–0.76

TABLE 8.—IMPACT OF REQUIREMENT FOR CALIBRATION VERIFICATION

Total .......................................................................... .................... .................... .................... .................... .................... 16.98

Methodology In estimating the cost of materials for applicable subspecialties, through

TABLE 10.—CHANGE IN COST PER TEST FOR REVISED BACTERIOLOGY QC REQUIREMENTS

Total ............................................... .................... ...................... .................... .................... .................... .................... ¥2,273.84

TABLE 11.—CHANGE IN COST PER TEST FOR REVISED MYCOBACTERIOLOGY QC REQUIREMENTS

Total ........................... .................... ........................................... .................... .................... .................... .................... +4,252.56

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