Medicare, Medicaid, and CLIA Programs; Laboratory Requirements Relating to Quality Systems and Certain Personnel Qualifications

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Medicare & Medicaid Services

Centers for Disease Control and Prevention

42 CFR Part 493

[CMS-2226-F]

RIN 0938-AK24

Medicare, Medicaid, and CLIA Programs; Laboratory Requirements Relating to Quality Systems and Certain Personnel Qualifications

AGENCY:

Centers for Disease Control and Prevention (CDC) and Centers for Medicare & Medicaid Services (CMS), HHS.

ACTION:

Final rule.

SUMMARY:

This final rule revises and responds to comments on certain laboratory requirements issued pursuant to the Clinical Laboratory Improvement Amendments of 1988 (CLIA), Pub. L. 100-578. Specifically, this final rule sets forth requirements for certain quality control (QC) provisions and personnel qualifications; consolidates and reorganizes the requirements for patient test management, QC, and quality assurance; and changes the consensus required for grading proficiency testing challenges.

To ensure a smooth transition to the new provisions for directors of high complexity testing who are not board certified (but who have doctoral degrees), we will not be holding facilities out of compliance with the provisions of the rule concerning directors who are not board certified until the effective date of this new rule, to the extent the facilities are otherwise in compliance with the requirements for laboratory directors.

EFFECTIVE DATES:

This final rule is effective on April 24, 2003, except § 493.1443(b)(3) is effective on February 24, 2003.

Compliance Dates:

To ensure a clear transition from the board certification provisions of the former rule at 42 CFR 493.1443(b)(2) that have a compliance date of December 31, 2002 (as set forth in 65 FR 82941), we will not be holding facilities out of compliance with the former rule until the effective date of the parallel provisions of this new rule to the extent that facilities are otherwise in compliance with the regulations for laboratory directors.

FOR FURTHER INFORMATION CONTACT:

Rhonda S. Whalen (CDC), (770) 488-8155, Judith A. Yost (CMS), (410) 786-3531.

SUPPLEMENTARY INFORMATION:

Copies:

To order copies of the

Federal Register

containing this document, send your request to: New Orders, Superintendent of Documents, P.O. Box 371954, Pittsburgh, PA 15250-7954. Specify the date of the issue requested and enclose a check or money order payable to the Superintendent of Documents, or enclose your Visa or Master Card number and expiration date. Credit card orders can also be placed by calling the order desk at (202) 512-1800 or by faxing to (202) 512-2250. The cost for each copy is $9. As an alternative, you can view and photocopy the

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This

Federal Register

document is also available from the

Federal Register

online database through GPO Access, a service of the U.S. Government Printing Office. This Web site address is:

http://www.access.gpo/nara/index.html.

I. Background

On February 28, 1992, we published a final rule with comment period in the

Federal Register

(57 FR 7002) that set forth the requirements for laboratories that are subject to the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

Under the provisions of the sentence following section 1861(s)(15) through 1861(s)(17) of the Social Security Act, (the Act) any laboratory that wants to be paid for services furnished to Medicare beneficiaries must meet the requirements of section 353 of the Public Health Services Act. Subject to specified exceptions, all laboratories, regardless of whether they receive payment from the Medicare or Medicaid programs must have a current and valid CLIA certificate to test human specimens. The February 28, 1992 final rule with comment period established uniform requirements based on the complexity of testing performed by laboratories regardless of the laboratory's location, size, or type. In the interest of public health, we included requirements in the February 28, 1992 final rule with comment period to ensure the quality of laboratory services.

We recognized that it would take time and resources for laboratories to understand and to implement the new requirements contained in the February 28, 1992 final rule with comment period. This final rule completes the phase-in of certain requirements where the comments supported taking this action.

The phased-in provision included quality control (QC) requirements applicable to moderate complexity tests and the date by which an individual with a doctorial degree must possess board certification to qualify as a director of a laboratory that performs high complexity testing.

During the phase-in, the Food and Drug Administration (FDA) was to establish a process to review and clear manufacturers' QC instructions for CLIA QC purposes. Because the CLIA program is user fee funded, we decided it would be prudent to wait until the phase-in period ended before implementing the FDA QC review. This afforded us the survey experience necessary to determine whether an additional FDA review process beyond that already in place as part of the premarket review would be of benefit to laboratories. We realized through our experience inspecting laboratories that an additional FDA review would not be of such benefit. We decided to remove this prospective provision. Therefore, we are removing all references to the FDA CLIA QC clearance process that was not implemented.

The phase-in effective dates contained in the February 28, 1992 final rule with comment period were further extended in the final rules with comment period published on December 6, 1994 in the

Federal Register

(59 FR 62606), May 12, 1997 in the

Federal Register

(62 FR 25855), October 14, 1998 in the

Federal Register

(63 FR 55031), and December 29, 2000 in the

Federal Register

(65 FR 82941).

The extensions allowed previously unregulated laboratories time to understand and implement these requirements. The extensions also provided the Department of Health and Human Services (HHS) additional time to issue revised QC requirements, review board certification program requests for approval, and ensure that laboratory directors with a doctoral degree had sufficient time to successfully complete the requirements for board certification.

On December 28, 2001, we published a proposed rule in the

Federal Register

(66 FR 67163) seeking comments on provisions to revise and expand the qualification requirements by which an individual with a doctoral degree in a chemical, physical, biological, or clinical laboratory science from an accredited institution may qualify to serve as a director of a laboratory performing high complexity testing. The

three proposed alternative qualification pathways were as follows:

• On or after January 1, 2003, be certified and continue to be certified by a board approved by HHS.

• Before January 1, 2003, must have served or be serving as a director of a laboratory performing high complexity testing and must have at least 2 years of laboratory training or experience, or both; and 2 years experience directing or supervising high complexity testing.

• Have at least 6 years of laboratory training or experience, or both, including 2 years of experience directing or supervising high complexity testing.

In this final rule, effective April 24, 2003, all laboratories must meet and follow the QC requirements. In addition, we are setting forth qualification requirements for an individual with a doctoral degree to serve as a director of a laboratory performing high complexity testing. Effective February 24, 2003, an individual with a doctoral degree may qualify to serve as a director of a laboratory that performs high complexity testing if he or she is certified and continues to be certified by a board approved by HHS; or before the effective date of this rule, has served or is serving as a director of a laboratory performing high complexity testing and has acquired at least 2 years of laboratory training or experience, or both, and 2 years of experience directing or supervising high complexity testing.

The qualification requirements for high complexity laboratory directors that are contained in this final rule will become effective February 24, 2003. To ensure a smooth transition to these new provisions, we will not be holding facilities out of compliance with the Board certified regulations of the former rule until the effective date of this new rule, to the extent the facilities are otherwise in compliance with the regulations for laboratory directors.

In addition, we are addressing the comments received in response to the February 28, 1992 final rule with comment period concerning part 493 of title 42 of the Code of Federal Regulations (CFR), subparts I, J, K, M, and P; comments received in response to the date-extension rules for certain provisions of subparts K and M; and comments to the December 28, 2001 proposed rule regarding qualification requirements for directors of laboratories performing high complexity testing.

II. Highlights and Organization of Final Rule

This regulation contains revisions to part 493 of title 42 of the CFR. We have renamed, reorganized, and consolidated similar requirements into one section, deleted duplicate requirements, and reworded numerous requirements to maintain and/or clarify their original intent, making the revised regulation easier to read and understand. In addition to specific changes to subparts I, J, K, M, and P, applicable technical and conforming changes were also made to other subparts.

The organization of this regulation now reflects the flow of a patient specimen through the laboratory, that is, from receipt of the specimen with the test request through test performance and test result reporting. In addition, this final rule more accurately describes the testing requirements and laboratory assessment activities.

In this final rule, the former Subpart I—Proficiency Testing Programs for Tests of Moderate Complexity (Including the Subcategory), High Complexity, or Any Combination of These Tests has been renamed Proficiency Testing Programs for Nonwaived Testing. In addition, in each specialty and subspecialty area of the subpart, we are restoring the requirement for the 80 percent agreement used by proficiency testing programs prior to the February 28, 1992 final rule with comment period.

The requirements formerly in Subpart J—Patient Test Management for Moderate Complexity (Including the Subcategory), High Complexity, or Any Combination of These Tests; Subpart K—Quality Control for Tests of Moderate Complexity (Including the Subcategory), High Complexity, or Any Combination of These Tests; and Subpart P—Quality Assurance for Moderate Complexity (Including the Subcategory) or High Complexity Testing, or Any Combination of These Tests, are consolidated and reorganized into a new Subpart J—Facility Administration for Nonwaived Testing, and Subpart K—Quality Systems for Nonwaived Testing.

As revised by this issuance, subpart J consolidates and clarifies the facility administration requirements for laboratories performing nonwaived testing. These include requirements for facility space, utilities and safety, transfusion services, and record and specimen retention. Also, subpart J now specifies that laboratories must comply with Federal, State, and local laboratory requirements. This will allow CMS to support a Federal, State, or local government that seeks to protect the public from actions it finds would be detrimental to public health. In addition, the requirements formerly at § 493.1111 (now at § 493.1242(c)) have been revised to allow CLIA-certified laboratories to refer specimens to laboratories operated under the Veterans Administration (VA), the Department of Defense (DOD), and CLIA-exempt laboratories within a State whose licensure program has been granted approval under subpart E.

Requirements pertaining to the total testing process (preanalytic, analytic, and postanalytic) are now in subpart K. Specifically, subpart K has been revised to eliminate the QC requirements formerly at § 493.1202 and provisions pertaining to the FDA review and approval of manufacturers' test system QC for CLIA purposes as specified at § 493.1203 in the February 28, 1992 final rule with comment period. Also, subpart K is now structured to correlate with the movement of a specimen through the laboratory from acquisition to examination or testing, and reporting of results. The requirements were not substantively changed to correspond to the testing process, but we did eliminate redundant requirements and revise others for clarification.

In addition, subpart K now incorporates the requirements formerly in Subpart P—Quality Assurance; Moderate Complexity (Including the Subcategory) or High Complexity Testing, or Any Combination of These Tests. These requirements are now located under the appropriate sections in subpart K, that is, General Laboratory Systems, Preanalytic Systems, Analytic Systems, and Postanalytic Systems. We listed the quality assurance (renamed quality assessment (QA) to more clearly reflect the activities performed) activities for each phase of testing. For example, QA requirements for preanalytic activities, such as monitoring the medical necessity and completeness of test request information solicited and obtained by the laboratory, now appear at the end of the preanalytic section of subpart K under § 493.1249. We believe that integrating the QA requirements into the various phases of the testing process enhances the understanding of the vital and important role QA plays in ensuring that quality services are provided by the laboratory throughout the entire testing process. To further emphasize and clarify the essential components of a comprehensive QA program, we are reiterating in each assessment section the laboratory's responsibility to: (1) Establish and follow written polices and procedures for an ongoing mechanism to monitor and assess each of its activities; (2) take corrective actions, as necessary, based on these assessments; (3) review the effectiveness of the assessments and corrective actions

taken; (4) revise policies and procedures, as necessary, to prevent recurrences of problems; (5) discuss the assessment activities and findings with the appropriate staff; and (6) document all assessment activities. To ensure the clarity of this final rule, many of the QA requirements from the former subpart P had to be rewritten.

To conform with the names of the new subparts I, J, and K, the former Subpart M—Personnel for Moderate Complexity (Including the Subcategory) and High Complexity Testing has been renamed Personnel for Nonwaived Testing. In subpart M, we are finalizing the qualification requirements for directors of laboratories performing high complexity testing at § 493.1443(b)(3). In addition, we are revising § 493.1443(b)(3)(i) by removing the reference to specific boards approved by HHS. All HHS-approved boards are listed on the Internet at

http://cms.hhs.gov/clia/dirc/con.asp.

HHS-approved boards will also be listed in Appendix C of the State Operations Manual (CMS Pub. 7), subpart M. This change will allow greater flexibility to update the list of HHS-approved boards. Also, we are announcing two new HHS-approved boards; the National Registry for Clinical Chemistry at the doctoral level and the American Board of Forensic Toxicology.

To clarify these changes, we have provided a distribution table, which contains a detailed list of sections that have been removed or redesignated.

III. Distribution Table

The following crosswalk table enables the reader to easily locate where the requirements from the former rule have been relocated. It lists the former section titles along with the section titles as they appear in this final rule. In addition, the reorganized regulation now follows the path of patient specimens as they proceed through the clinical laboratory. This organizational structure was adopted at the recommendation of the Clinical Laboratory Improvement Advisory Committee to assist laboratories in better understanding the basic CLIA requirements.

Table.—Crosswalk

Former requirements and former sections (part 493, subparts J, K, M, and P)

Requirements in this final rule (part 493, subparts J, K, and M)

Sections in this final rule

Patient test management; moderate complexity (including the subcategory), or high complexity 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 handling:

§ 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);

Procedure manual

493.1251(b)(1)

§ 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)

§ 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 complexity 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;

Procedure manual

493.1251(b)(7)

Moderate or high complexity testing, or both, Effective from September 1, 1992 to December 13, 2000:

§ 493.1202(a)

Facility administration

§§ 493.1100;

Subpart K—Quality systems for nonwaived testing

493.1201 through 493.1227

§ 493.1202(b)

Facility administration

§§ 493.1100;

Subpart K—Quality systems for nonwaived testing

493.1201 through 493.1227

§ 493.1202(c)

Facility administration

§§ 493.1100;

Subpart K—Quality systems for nonwaived testing

493.1201 through 493.1227

§ 493.1202(c)(1)

Test systems, equipment, instruments, reagents, materials, and supplies

§§ 493.1252(a);

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 procedures

§ 493.1255

§ 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 effective 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, reagents, materials, and supplies:

§ 493.1205—Introductory text

Facility Test systems, equipment, instruments, reagents, materials, and supplies

§§ 493.1101(b); 493.1252

§ 493.1205(a)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(a)

§ 493.1205(b)

Facilities

§ 493.1101(b)

§ 493.1205(c)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(b)

§ 493.1205(c)(1)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(b)

§ 493.1205(c)(1)(i)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(b)(1)

§ 493.1205(c)(1)(ii)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(b)(2)

§ 493.1205(c)(1)(iii)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(b)(3)

§ 493.1205(c)(1)(iv)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(b)(4)

§ 493.1205(c)(2)

Corrective actions

§ 493.1282(b)(3)

§ 493.1205(d)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(c)

§ 493.1205(d)(1)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(c)(1)

§ 493.1205(d)(2)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(c)(2)

§ 493.1205(d)(3)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(c)(3)

§ 493.1205(d)(4)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(c)(4)

§ 493.1205(e)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 493.1252(d)

§ 493.1205(e)(1)

Test systems, equipment, instruments, reagents, materials, and supplies

§§ 493.1252(d);

Immunohematology

493.1271(b)

§ 493.1205(e)(2)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 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)(2)

Procedure manual

§ 493.1251(b)(2)

§ 493.1211(b)(3)

Procedure manual

§§ 493.1251(b)(3);

Histocompatibility

493.1278(d)(7)

§ 493.1211(b)(4)

Procedure manual

§ 493.1251(b)(4)

§ 493.1211(b)(5)

Procedure manual

§ 493.1251(b)(5)

§ 493.1211(b)(6)

Procedure manual

§ 493.1251(b)(6)

§ 493.1211(b)(7)

Procedure manual

§ 493.1251(b)(7)

§ 493.1211(b)(8)

Procedure manual

§ 493.1251(b)(8)

§ 493.1211(b)(9)

Procedure manual

§ 493.1251(b)(9)

§ 493.1211(b)(10)

Procedure manual

§ 493.1251(b)(10)

§ 493.1211(b)(11)

Procedure manual

§ 493.1251(b)(11)

§ 493.1211(b)(12)

Procedure manual

§ 493.1251(b)(12)

§ 493.1211(b)(13)

Specimen submission, handling, and referral

§§ 493.1242(a)(4);

Procedure manual

493.1251(b)(1)

§ 493.1211(b)(14)

Procedure manual

§ 493.1251(b)(13)

§ 493.1211(b)(15)

Procedure manual

§ 493.1251(b)(14)

§ 493.1211(b)(16)

Procedure manual

§ 493.1251(b)(1)

§ 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 performance specifications:

§ 493.1213—Introductory text

Removed

§ 493.1213(a)

Establishment and verification of performance specifications

§ 493.1253(a)

§ 493.1213(b)(1)

Removed

§ 493.1213(b)(2)

Establishment and verification of performance specifications

§§ 493.1253(b)(1) and (2)

§ 493.1213(b)(2)(i)

Establishment and verification of performance specifications

§§ 493.1253(b)(1) and (b)(2)

§ 493.1213(b)(2)(i)(A)

Establishment and verification of performance specifications

§§ 493.1253(b)(1)(i)(A) and (b)(2)(i)

§ 493.1213(b)(2)(i)(B)

Establishment and verification of performance specifications

§§ 493.1253(b)(1)(i)(B) and (b)(2)(ii)

§ 493.1213(b)(2)(i)(C)

Establishment and verification of performance specifications

§ 493.1253(b)(2)(iii)

§ 493.1213(b)(2)(i)(D)

Establishment and verification of performance specifications

§ 493.1253(b)(2)(iv)

§ 493.1213(b)(2)(i)(E)

Establishment and verification of performance specifications

§§ 493.1253(b)(1)(i)(C) and (b)(2)(v)

§ 493.1213(b)(2)(i)(F)

Establishment and verification of performance specifications

§§ 493.1253(b)(1)(ii) and (b)(2)(vi)

§ 493.1213(b)(2)(i)(G)

Establishment and verification of performance specifications

§ 493.1253(b)(2)(vii)

§ 493.1213(b)(2)(ii)

Establishment and verification of performance specifications

§ 493.1253(b)(3)

§ 493.1213(c)

Establishment and verification of performance specifications

§ 493.1253(c)

Equipment maintenance and function checks:

§ 493.1215—Introductory text

Removed

§ 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 procedures:

§ 493.1217—Introductory text

General Provisions—Definitions Calibration and calibration verification procedures

§§ 493.2; 493.1255

§ 493.1217(a)

Removed

§ 493.1217(b)—Lead-in only

Removed

§ 493.1217(b)(1)

Calibration and calibration verification procedures

§ 493.1255(a)

§ 493.1217(b)(1)(i)

Calibration and calibration verification procedures

§ 493.1255(a)(1)

§ 493.1217(b)(1)(ii)

Calibration and calibration verification procedures

§ 493.1255(a)(2)

§ 493.1217(b)(1)(ii)(A)

Calibration and calibration verification procedures

§ 493.1255(a)(2)(ii)

§ 493.1217(b)(1)(ii)(B)

Calibration and calibration verification procedures

§ 493.1255(a)(2)(i)

§ 493.1217(b)(1)(iii)

Calibration and calibration verification procedures

§ 493.1255(a)(3)

§ 493.1217(b)(2)

Calibration and calibration verification procedures

§ 493.1255(b)

§ 493.1217(b)(2)(i)

Calibration and calibration verification procedures

§ 493.1255(b)(1)

§ 493.1217(b)(2)(ii)

Calibration and calibration verification procedures

§ 493.1255(b)(2)

§ 493.1217(b)(2)(ii)(A)

Calibration and calibration verification procedures

§ 493.1255(b)(2)(i)

§ 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 procedures

§ 493.1255(b)(2)(ii)

§ 493.1217(b)(2)(ii)(C)

Calibration and calibration verification procedures

§ 493.1255(b)(3)

§ 493.1217(b)(2)(ii)(C)(1)

Calibration and calibration verification procedures

§ 493.1255(b)(3)(i)

§ 493.1217(b)(2)(ii)(C)(2)

Calibration and calibration verification procedures

§ 493.1255(b)(3)(ii)

§ 493.1217(b)(2)(ii)(C)(3)

Calibration and calibration verification procedures

§ 493.1255(b)(3)(iii)

§ 493.1217(b)(2)(ii)(C)(4)

Calibration and calibration verification procedures

§ 493.1255(b)(3)(iv)

§ 493.1217(b)(3)

Calibration and calibration verification procedures

§ 493.1255(a) and (b)

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

Histopathology

§§ 493.1256(e)(3);

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

Test report

§§ 493.1105(a)(6);

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, reagents, material, and supplies performance

493.1252(b);

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 procedures

493.1255(a) and (b);

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, reagents, material, and supplies

493.1252(a)

§ 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, reagents, materials, and supplies

§ 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

Control procedures

§§ 493.1213;

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, Histopathology

§§ 493.1101(e); 493.1105(a)(7)(iii); 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)—Lead-in only

Removed

§ 493.1265(a)(3)(i)

Test systems, equipment, instruments, reagents, materials, and supplies

§ 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, Histocompatibility; Test records

§§ 493.1232; 493.1278(a)(2) 493.1283(a)(1)

§ 493.1265(a)(4)

Histocompatibility

§ 493.1278(a)(3)

§ 493.1265(a)(5)

Test systems, equipment, instruments, reagents, materials, and supplies

§§ 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, reagents, materials, and supplies

§ 493.1252(b)

§ 493.1265(a)(9)—Lead-in only

Removed

§ 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(b)(2)

Histocompatibility

§ 493.1278(f)(1)

§ 493.1265(b)(3)

Histocompatibility

§ 493.1278(f)(3)

§ 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 Subpart M

§ 493.1103; § 493.1449(b) and (q)

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; Immunohematology

§§ 493.1103(d); 493.1271(e)(1)and (e)(2)

Quality assurance for Moderate Complexity (including the Subcategory) or High Complexity Testing, or Any Combination of These Tests:

§ 493.1701

Introduction; General laboratory systems; General laboratory systems assessment; Preanalytic Systems; Test request; Preanalytic systems assessment; Analytic Systems; Analytic systems assessment; Postanalytic Systems; Postanalytic systems assessment

§§ 493.1200; 493.1230; 493.1239; 493.1240; 493.1241(e); 493.1249; 493.1250; 493.1289; 493.1290; 493.1299

Patient test management assessment:

§ 493.1703—Introductory text

General laboratory systems; General laboratory systems assessment; Preanalytic Systems; Preanalytic systems assessment; Postanalytic Systems; Postanalytic systems assessment

§§ 493.1230; 493.1239(a) and (b); 493.1240; 493.1249(a) and (b); 493.1290; 493.1299(a) and (b)

§ 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 assessment

§§ 493.1291(a), (g), and (h); 493.1299(a) and (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 assessment

§§ 493.1250; 493.1289(a) and (b)

§ 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 systems assessment

§§ 493.1289(a) and (b); 493.1299(a) and (b)

Proficiency testing assessment:

§ 493.1707

General laboratory systems; Evaluation of proficiency testing; General laboratory systems assessment

§§ 493.1230; 493.1236(a)(1); 493.1239(a) and (b)

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 assessment

§§ 493.1281(b); 493.1289(a) and (b)

§ 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 assessment

§§ 493.1281(b)(5); 493.1289(a) and (b)

Personnel assessment:

§ 493.1713

Personnel competency assessment policies; General laboratory systems assessment

§§ 493.1235; 493.1239(a) and (b)

Communications:

§ 493.1715

Communications; General laboratory systems assessment

§§ 493.1234; 493.1239(a) and (b)

Complaint investigations:

§ 493.1717

Complaint investigations; General laboratory systems assessment

§§ 493.1233; 493.1239(a) and (b)

Quality assurance review with staff:

§ 493.1719

General laboratory systems assessment; Preanalytic systems assessment; Analytic systems assessment; Postanalytic systems assessment

§§ 493.1239(b) and (c); 493.1249(b) and (c); 493.1289(b) and (c); 493.1299(b) and (c)

Quality assurance records:

§ 493.1721

Retention requirements; General laboratory systems assessment; Analytic systems assessment

§§ 493.1105(a)(5) and (b); 493.1239(c); 493.1249(c); 493.1289(c); 493.1299(c)

IV. Analysis and Responses to Public Comments

We received numerous comments on the final rule with comment period published on February 28, 1992 in the

Federal Register

. These comments were from State agencies, proficiency testing programs, professional organizations, the Clinical Laboratory Improvement Advisory Committee (CLIAC), laboratories, physicians, and the general public. Summaries of the public comments received and our responses to those comments are set forth below.

Subpart I—Proficiency Testing Programs for Tests of Moderate Complexity (Including the Subcategory), High Complexity, or Any Combination of These Tests

We received a number of comments on the topic of proficiency testing. We intend to publish a notice of proposed rulemaking addressing proficiency testing issues in more detail in the future. We have, however, determined that it would be appropriate to include in this final rule a change that we believe is necessary to improve the operation of the CLIA proficiency testing program, related to the percentage of required agreement among participant or reference laboratories. Thus, we are addressing only one of the changes requested by the commenters and recommended by the CLIAC.

Specific comments received and response to comments regarding subpart I are set forth below.

Comment:

A few commenters, professional organizations, and proficiency testing programs expressed their concerns over the change to a 90 percent consensus requirement to be reached before a proficiency testing sample could be graded. Commenters felt there should be a grade assigned to their samples. One commenter stated that their laboratory paid for samples, so grading should be required. Proficiency testing programs had similar opinions. The CLIAC recommended reducing the consensus required for grading proficiency testing challenges to decrease the number of ungradeable samples as ungraded proficiency testing is not effective in assisting laboratories in their quality assessment of test performance.

Response:

We agree with the commenters and are changing the percentage of required agreement among participant or referee laboratories to 80 percent in the specialties and subspecialties where 90 percent agreement was previously required.

Subpart J—Patient Test Management for Moderate Complexity (Including the Subcategory), High Complexity, or Any Combination of These Tests

Following publication of the final rule with comment period, we received approximately 150 comments regarding subpart J. The comments were in response to the requirements for specimen submission and handling; test requisition including oral requests and authorized persons; and test records and test reports, including confidentiality and referral of specimens. The majority of the commenters disagreed with some portion of the requirements and some commenters requested clarification of certain requirements while others offered specific revised language.

Specific comments received and responses to comments regarding subpart J are set forth below.

Comment:

A number of State agencies disagreed with our removal of the requirement that laboratories comply with applicable Federal, State, and local laws.

Response:

We agree with the commenters and are reinstating the requirement now at § 493.1101(c). As part of the partnering relationship with State agencies and local governments, the reinstatement of this requirement will allow us to support a State or local government that seeks to protect the public from actions it finds would be detrimental to public health.

Comment:

Some commenters disagreed with requiring written authorization for oral test requests, describing the difficulties that this requirement causes.

Response:

We acknowledge that when a laboratory asks that an oral request for patient testing be followed with a written request, there is no guarantee that one will be received. On January 19, 1993, we published a technical correction in the

Federal Register

(58 FR 5215) and (58 FR 5229) that amended the requirement formerly at § 493.1105. This requirement, now at § 493.1241(b), states that oral requests for laboratory tests are permitted only if the laboratory requests written or electronic authorization for testing within 30 days of the oral request and documents the efforts made to obtain a written or electronic authorization.

Comment:

We received several comments recommending information the laboratory should solicit and obtain on the test requisition. Specifically, the commenters believe the age and sex of the patient, time of specimen collection, and the specimen source should be included since they are pertinent to either how the laboratory processes the specimen and/or how the test results are interpreted.

Response:

We agree with the commenters. The requirement, formerly at § 493.1105(f), requires the laboratory to ensure that the requisition or test authorization includes any additional information relevant and necessary for accurate and timely testing and result reporting (for clarity, we are adding “interpretation” if applicable to this requirement). The requirement, now at § 493.1241(c)(3), specifies that the laboratory must request the patient's sex and age or date of birth as normal values and interpretation of test results are often dependent on this information. Concurrently, we are redesignating age or date of birth requirements, formerly at § 493.1105(e), for Pap smear requisitions to test requests (now at § 493.1241(c)(3)). The time of specimen collection must also be requested when it is relevant for the testing to be performed. For example, this information is important when interpreting the results of peak and trough therapeutic drug assays. In addition, we are requiring that specimen source, when appropriate, be solicited on the test requisition. Specimen handling, preservation, and preparation (for example, use of proper transfer media, inoculation of media in microbiology and clinical cytogenetics, and the application of appropriate normal values reported with patient test results) are dependent on the origin of the specimen. Therefore, we are including specimen source, when appropriate, as part of the laboratory's submission, handling, and referral procedures (now at § 493.1242(a)(3)). We are also requiring specimen source to be included on the test report if warranted (now at § 493.1291(c)(5)). This routine laboratory practice was inadvertently omitted from the final rule with comment period.

Comment:

One organization representing members of the laboratory community objected to the amount of information that a laboratory must have on the test requisition, specifically the information that is needed when submitting a Pap smear. The organization stated that laboratories do not have access to patient records and are dependent on the authorized person ordering the test to provide this information. The organization agreed the information was important but assumed we would prohibit testing if all information was not obtained by the laboratory.

Response:

We agree with the commenter that the information being requested is important. Therefore, we are retaining the test request

requirements formerly at § 493.1105, (now at § 493.1241(c)) as relevant information necessary for proper test performance and interpretation. The test requisition requirements do not prohibit laboratories from performing the testing if the requested information is missing. Although we expect laboratories to obtain this information when possible, the potential negative impact of the missing information on the test results may be addressed or noted on the report.

Comment:

One State health department requested modification of the requirement for recording the time of specimen receipt into the laboratory, stating we should require the time of receipt only if it is pertinent to sample integrity, test method, or procedure.

Response:

We disagree with the commenter. Recording the date and time of specimen receipt enables the laboratory to determine the elapsed time between specimen receipt and reporting of patient test results. It also provides a mechanism to monitor transportation times for specimens referred to the laboratory. Therefore, we are retaining this requirement formerly at § 493.1107(b) (now at § 493.1242(b)).

Comment:

One commenter stated the final rule with comment period did not require a person's name or unique identifier on the test report.

Response:

We agree with the commenter that the final rule with comment period did not specifically require a patient's name or unique identifier as part of the test report formerly at § 493.1109. Therefore, we are adding at § 493.1291(c)(1), a requirement for the laboratory report to include the patient's name with an identification number, or a unique patient identifier and identification number to ensure positive patient identification. The patient's name alone is not a unique identifier, and when used on the test report, the patient's name must be accompanied by an identification or accession number. When a patient's name is not used for confidentiality purposes, or when the identity of the person is not known, a unique patient identifier must be submitted with the specimen. The laboratory must also use an identification number. In reviewing the report requirements formerly at § 493.1109(b), interpretation was omitted. Therefore, we are adding interpretation to the test report requirements at § 493.1291(c)(6) for those test results that require supplemental information.

Comment:

Some commenters disagreed with requiring the name and address of the laboratory performing the test on the test report. They believed that too much information would make the report crowded and confusing. Another comment received from a professional organization acknowledged the benefit of this requirement, but stated its application to cumulative reports causes disruption of data presentation and utility of the report and, in some cases, the information cannot reasonably be included.

Response:

We agree the name and address of the laboratory performing the test is an essential piece of information that must be included on the test report. It provides a contact for the individual who requested or is using the test results when additional information is needed for result interpretation and patient care. If a laboratory determines its reports are crowded or confusing, it has complete latitude and responsibility to reorganize the report in a manner that will correct the problem as specified formerly at § 493.1703 (now at § 493.1299). A laboratory that generates cumulative reports may use a single character identifier (for example, an asterisk or subscript) to identify a particular reference laboratory that performed the test. This information (the name and address of the reference laboratory) may be defined on a subsequent page or on the back of the report. Laboratories may develop other formats to meet this requirement. However, we are retaining the requirement formerly at § 493.1109(b) (now at § 493.1291(c)(2)) to include the name and address of the laboratory where the test was performed.

Comment:

One commenter questioned the appropriateness of maintaining test records in the patient's chart or medical record.

Response:

The CLIA regulation does not preclude laboratories from storing test records in a patient's chart or medical record; however, records must include the following:

• Test analysis (including instrument printouts, if applicable).

• Identity of the personnel performing the test.

To retain this type of information in a patient's chart or medical record may be cumbersome and impractical for QA activities; however, it is at the discretion of the laboratory.

Comment:

One commenter questioned whether computer records of reports are acceptable in lieu of paper files.

Response:

The requirement formerly at § 493.1109(h) specifies that all test reports or an exact duplicate of each test report must be maintained by the laboratory in a manner that permits ready identification and timely accessibility. The information contained on the test report may be manually written, generated by an electronic system, maintained on microfilm, or any other means, provided it contains all of the information that was on the original test report. Therefore, we are deleting the reference to “exact duplicate” that was contained in the former § 493.1109(h), and amending the language now at § 493.1291(j) to clarify that the laboratory must be able to retrieve a copy of the original report. We are also making a conforming change in the retention requirement for test reports (now at § 493.1105(a)(6)).

Comment:

Many commenters stated that the removal of the subpart on laboratory information systems (LIS) was inappropriate and not logical considering the current and future direction of collection and dissemination of laboratory data. Other commenters indicated that the current method of reporting patient results and the laboratory computer system was overlooked.

Response:

We agree with all of the commenters and are addressing some of the commenters' concerns pertaining to electronic patient and testing information by doing the following:

• Adding a requirement at § 493.1101(e) for laboratories to store and maintain records in a manner that ensures proper preservation. Proper storage of patient records that are collected in a LIS is essential for record preservation and accurate recall of patient information. Without proper storage and maintenance of records, the timeframes, identification, and the accessibility of records will not be possible.

• Incorporating a requirement at § 493.1241(e) for laboratories using LIS to ensure that the requisition information is accurately transcribed or entered. The laboratory may establish its own mechanism to meet this requirement, possibly through random checks or representative sampling of LIS patient testing information verified against that submitted on the original test request.

• Adding a requirement at § 493.1291(a) that requires laboratories to ensure patient test results are accurately and reliably sent from the point of data entry to the final report's destination in a timely manner. We are providing frequently encountered reporting scenarios that must be reviewed by the laboratory to ensure the accuracy and reliability of the transmitted patient result information.

• Requiring at § 493.1291(c) that the date of the test report be identified on the report. This date must be maintained as the date testing results

were generated as a final report and must not change on copies reported at a later date.

The above requirements are intended to respond in part to the commenters' requests. We intend to publish, at a later date, a rule specific to laboratory information systems. For example, requirements for the establishment and verification of system programs, system security, system and device maintenance, system operator functions and responsibilities, and system backups.

Comment:

One commenter was concerned about limited record storage space on-site and asked if off-site storage of records would be acceptable provided the laboratory was able to produce these records during an inspection.

Response:

Records may be stored at a place of the laboratory's choosing providing the storage is appropriate and the laboratory can produce the documents within a reasonable time during the course of an inspection as required at § 493.1773(c).

Comment:

Several commenters disagreed with the requirement to retain records for a minimum of 2 years or 5 years, depending upon the type of record. A professional organization questioned whether instrument printouts must be retained for 2 years if appropriate data are saved in a retrievable manner. Other commenters felt that 3 months, and, in one case, 6 months, would be sufficient time to retain instrument printouts.

Response:

We believe all records related to testing, for example, records of test requests, patient test records including, if applicable, instrument printouts, and copies of test reports are essential for the ongoing QA reviews performed by the laboratory. Instrument printouts are test records and are sometimes used as test reports and for these reasons must be retained for the appropriate length of time unless all information is duplicated in another record system. Additionally, CLIA requires biennial certification that includes an inspection of the laboratory's activities for compliance with CLIA requirements by either an on-site inspection of the laboratory or a self-assessment inspection through use of the Alternate Quality Assessment Survey (AQAS). These inspections require a review of the testing performed by the laboratory since the previous biennial inspection. Two years is the minimum amount of time records must be retained to ensure that they are available for review at inspection. However, we are clarifying the record retention requirements for immunohematology and blood and blood products formerly at § 493.1107 introductory text and § 493.1221 (now at § 493.1105(a)(3)(ii)) and formerly at § 493.1109 introductory text (now at § 493.1105(a)(6)(i)) to ensure consistency with the FDA requirements for these types of records.

Subpart K—Quality Control for Tests of Moderate Complexity (Including the Subcategory), High Complexity, or Any Combination of These Tests

In the final rule with comment period, the QC rules are located in subpart K and include the general QC requirements and specific QC requirements for each specialty and subspecialty of testing. A phase-in period provided less stringent general QC requirements for unmodified moderate complexity tests approved by the FDA through the premarket notification 510(k) or premarket approval (PMA) process.

Following publication of the final rule with comment period, we received approximately 1,030 comments. Of these comments, 280 were directed at the general QC requirements, 67 pertained to the specialty and subspecialty QC requirements, and approximately 680 pertained to cytology and histopathology requirements. The majority of the comments disagreed with some portion of the requirements, indicating that the final rule with comment period was either too restrictive or too lenient. Some commenters requested clarification of certain requirements, while others offered specific revised language. A few comments agreed with the final rule with comment period, while others indicated the requirements had either been misinterpreted or misread. We addressed some of the commenters' issues in a technical correction published on January 19, 1993 in the

Federal Register

(58 FR 5215).

In evaluating the comments and considering the types of revisions to make in this subpart, we obtained recommendations from the CLIAC and consulted with various professional organizations and laboratory personnel. In September 1996, we participated in public discussions at a 2-day meeting in Atlanta, Georgia. At the public meeting, manufacturers, laboratory organizations, and State representatives made presentations concerning QC principles, control materials and systems, manufacturers' recommendations, costs associated with control testing, and personnel implications. Their recommendation was to make changes to accommodate new technology. Our changes in this final rule are based on the advice and comments we received.

Specific comments and response to comments regarding subpart K are set forth below.

Comment:

We received mixed comments concerning the general QC requirements. Some commenters felt the QC requirements were burdensome and would increase the cost of testing and asked that these requirements be deleted or revised. Conversely, some commenters agreed with the requirements, indicating that QC is absolutely essential to producing accurate test results and is good laboratory practice. Others stated the requirements of subpart K were both reasonable and attainable. A few commenters requested further clarification.

Response:

We agree with the comments that QC procedures are essential to good laboratory practice and production of accurate test results. Control procedures verify that the patient results are substantially unaffected by day-to-day variation caused by the test system, environment, or operator. While the requirement for implementing QC may initially increase the cost of testing in some settings, it may decrease the long term cost as improved accuracy and reliability of testing reduces the need for retesting and unnecessary procedures or treatments.

Comment:

A manufacturer's organization requested that § 493.1202(c) be revised to include those products not subject to the FDA clearance process to allow laboratories performing these tests to meet the phase-in QC requirements.

Response:

We agree that the regulation needs to be revised to include these products, and provisions addressing these products were added in the revisions to the regulations published in the January 19, 1993 technical corrections (58 FR 5215). Since these products are not evaluated by the FDA, they could not be included under § 493.1202(c) but were added to § 493.1202(b) and subject to all applicable standards of subpart K.

Comment:

Comments were divided concerning the phase-in of the general QC requirements. Some commenters agreed with the phase-in while others were opposed. Some commenters felt that following manufacturers' instructions should be sufficient to meet the CLIA QC requirements. Others expressed concern that FDA would not complete the review and approval of manufacturers' QC instructions by September 1, 1994. Most commenters opposed the phase-in provision. Some

commenters were concerned that manufacturers' QC protocols cleared by the FDA might be less stringent than the CLIA QC requirements. Other commenters disagreed with having two sets of general QC requirements, and other commenters were confused about the phase-in requirements and requested clarification.

Response:

We implemented a phase-in of the general QC requirements to allow previously unregulated laboratories performing only FDA-approved or cleared, unmodified, and moderate complexity testing sufficient time to implement effective QC programs. During the phase-in, the FDA was to establish a process to review and clear manufacturers' QC instructions for CLIA QC purposes. Under this process, laboratories could meet certain CLIA QC requirements by following the FDA-approved manufacturers' QC instructions. On four occasions, we extended the phase-in of the general QC requirements that are currently in effect until December 31, 2002. However, because the CLIA program is user fee funded, we decided it would be prudent to wait until the phase-in period ended before implementing the FDA QC review. This afforded us the survey experience necessary to determine whether an additional FDA review would be of benefit to laboratories. We realized through our experience inspecting laboratories that an additional FDA review would not be of such benefit. Therefore, in this final rule, we are eliminating the phase-in requirements and establishing minimum general quality system requirements applicable to all nonwaived testing, regardless of complexity. In addition, we are removing all references to the FDA QC clearance process that was not implemented. However, we agree with the commenters that it is essential for laboratories to perform testing according to the manufacturers' test system instructions as required formerly at § 493.1202(c)(1) (now at § 493.1252(a)).

Comment:

A few comments were received in response to the environmental and safety requirements at § 493.1204. Some commenters indicated that the requirements were too lenient. Others were opposed to exempting moderate complexity testing from the requirements at § 493.1204 during the phase-in, stating that all laboratories should be subject to these requirements.

Response:

We agree with the commenters and therefore are retaining the requirement formerly at § 493.1204 (now at § 493.1101, subpart J) and applying it to both moderate and high complexity testing. In addition, we are providing some flexibility to the requirement formerly at § 493.1204(b) (now at § 493.1101(d)) that requires laboratories to post safety precautions. The revisions now require that safety procedures be accessible rather than posted.

Comment:

We received several comments concerning the requirements at § 493.1205. Most commenters opposed the requirement prohibiting the use of expired reagents. One commenter requested clarification of § 493.1205(c)(1) that requires the laboratory to define criteria for reagent and specimen storage conditions.

Response:

We understand the concerns expressed regarding the use of rare and expensive reagents and materials beyond their expiration dates. However, the manufacturer has the responsibility for establishing expiration dates that ensure the reagents and materials will perform properly when used for patient testing. In addition, any changes in the labeling of

in-vitro

diagnostics must comply with Food, Drug, and Cosmetic Act requirements. Therefore, we are not making any revisions to the requirement formerly at § 493.1205(e)(1) (now at § 493.1252(d)) prohibiting the use of expired reagents and other materials.

In regard to licensed biological and blood products, any exceptions to dating requirements must be granted by the FDA in the form of an amendment to the product license. In this final rule, we are consolidating all requirements pertaining to the immunohematological testing and distribution of blood and blood products (now at § 493.1271(b)).

We are adding language to the requirement formerly at § 493.1205(c)(1) to clarify how the laboratory establishes and uses its criteria for storing reagents and patient specimens. The requirement now at § 493.1252(b), states that the laboratory must define criteria for those conditions in the manufacturer's test system instructions, when available, that are essential for proper storage of reagents and specimens, and accurate and reliable test system operation and test result reporting. The criteria must be consistent with the manufacturers' instructions, if provided. These conditions must be monitored, documented, and include (1) water quality; (2) temperature; (3) humidity; and (4) electrical tolerances.

Comment:

One commenter agreed with the requirements at § 493.1211, Procedure manual. Another commenter suggested that the procedure manual requirements be deleted. Two commenters opposed permitting the use of the manufacturer's package insert to satisfy the requirements at §§ 493.1211(b)(1) through 493.1211(b)(13). Another commenter suggested that laboratories be required to retain each procedure's original specifications and instructions for use as provided by the manufacturer, and maintain a list of any alterations or changes in the procedure manual.

Response:

We disagree with the commenter who requested that the procedure manual requirements be deleted. All laboratories must maintain and follow procedure manual instructions in order to provide uniform patient testing. Therefore, we are retaining the requirements for a procedure manual now at § 493.1251. Laboratories may use the manufacturer's test system instructions to meet many of the procedure manual requirements, but must supplement them with any laboratory-specific information related to its testing and reporting practices. Examples are the laboratory's procedures for reporting patient test results, including panic values or alert values, corrective actions to follow when test systems become inoperable, and criteria for specimen referral. The use of the manufacturer's test system instructions to meet many of the procedure manual requirements is permitted to ensure that laboratories follow the manufacturer's instructions for patient testing and to minimize the burden on laboratories in developing procedure manuals.

For clarity and consistency, we are reiterating the requirements formerly at §§ 493.1103(a) and 493.1211(b)(14) (now at §§ 493.1242 and 493.1251) that the laboratory have written policies and procedures for specimen submission. In addition, we included language now at § 493.1251(b)(13) to clarify the use of laboratory information systems for entering patient test results.

In addition, we agree with the commenter that laboratories must have copies of test procedures. Therefore, we are retaining the requirement now at § 493.1251(e) that laboratories must maintain a copy of the procedure with the dates of initial use and discontinuance for 2 years after a procedure is no longer used.

Comment:

Several commenters opposed the requirement at § 493.1211 for the director to approve, date, and sign the procedure manual, approve any change in procedure, or re-approve the manual should there be a change in directorship. One commenter suggested that the requirement be revised to state each procedure must be approved by the director before patient testing.

Response:

The director is the individual ultimately responsible for the operation and administration of the

testing facility and is therefore responsible for authorizing all testing procedures and any alterations or revisions of these procedures. If a change in directorship occurs, re-approval of the manuals by the new director is necessary since he or she assumes responsibility for all testing procedures and any alterations or revisions of the procedures. We agree with the comment stating that each procedure should be approved by the director before patient testing. Therefore, we are revising the requirement formerly at § 493.1211(d) (now at § 493.1251(d)) to specify that the director reviews each procedure and change in procedure before use. We are also emphasizing that we do not expect laboratories to suspend testing for those procedures already in use that may not have been approved before patient testing. However, effective April 24, 2003, all alterations in current procedures and all newly implemented procedures must be reviewed and signed by the director before use.

In addition, we are revising the requirement formerly at § 493.1211(e) (now at § 493.1251(d)) to include the provision that requires procedures to be re-approved if the directorship changes. Section 493.1251(d) now states, “procedures and changes in procedures must be approved, signed, and dated by the current laboratory director before use.” If the directorship changes, the current director would not be expected to suspend testing to review the procedures in use or changes to procedures approved by the previous director. However, the current director must review all procedures in use by the laboratory in a timely manner.

Comment:

Approximately one third of the comments received disagreed with § 493.1213, Establishment and verification of method performance specifications. Some individuals opposed verifying the manufacturer's performance specifications for those methods cleared by FDA as meeting certain CLIA requirements for QC. One commenter disagreed with the requirement to establish performance specifications for those methods developed in-house, modified by the laboratory, or not cleared by FDA as meeting certain CLIA QC requirements. Another individual suggested that the standard be retroactive and apply to all test methods. One commenter asked that this standard be revised to state, “The provisions of this section are not retroactive for previously unregulated laboratories. Previously unregulated laboratories are not required * * *.”

Response:

We understand the commenters' concerns about the time and resources necessary to establish or verify performance specifications. However, these requirements ensure that the laboratory has either established test system performance specifications or verified that it can obtain the manufacturer's performance specifications in the laboratory's environment using the laboratory's testing personnel. In addition, establishment or verification of performance specifications are integral to the laboratory's establishment of appropriate and effective QC and calibration protocols. These protocols must include descriptions of the numbers, types, and concentrations of all calibration and control materials, as well as the performance intervals. Calibration and control protocols based on unverified performance specifications could result in poorly controlled and inaccurate testing. In the interest of establishing appropriate calibration and control practices and improving the reliability, accuracy, and usefulness of patient testing, we are retaining the requirements formerly at § 493.1213, and are now applying them to nonwaived testing at § 493.1253.

Laboratories employing methods (not modified by the laboratory) that have manufacturer-established performance specifications must demonstrate before reporting patient test results that they can obtain performance specifications for accuracy, precision, and reportable range of test results for the test system, comparable to those established by the manufacturer. The laboratory director must decide the extent to which these performance specifications are verified based on the method, testing conditions, and personnel performing the test.

In addition, we are clarifying when a laboratory must establish test system performance specifications (for example, laboratories using a test system in which the manufacturer does not provide performance specifications) now at § 493.1253(b)(2). Laboratories must, before reporting patient test results, establish, as applicable, performance specifications for the following performance characteristics: (1) Accuracy; (2) precision; (3) analytical sensitivity; (4) analytical specificity, including interfering substances; (5) reportable range of test results for the test system; (6) reference intervals (normal ranges); and (7) any other performance characteristic required for test performance.

Section 493.1253(b)(1) uses the term “FDA-cleared or approved test system” as defined (at § 493.2, Definition) in the November 9, 1997 revisions to the Food, Drug and Cosmetic Act (Pub. L. 105-115), to mean a test system cleared or approved by the FDA through either the premarket notification (510(k)) or premarket approval (PMA) process for

in-vitro

diagnostic use. This includes test systems exempt from FDA premarket clearance or approval.

Regulations do not have retroactive effect. The CLIA requirement's effective date became applicable to newly regulated laboratories on September 1, 1992. Those laboratories that were subject to regulations prior to this September 1, 1992 effective date were already required to validate test procedures under former Federal regulations before the CLIA requirements were implemented. This rule does not have a retroactive effect. Laboratories performing unmodified moderate complexity tests cleared or approved by the FDA are not required to retroactively verify the manufacturer's performance specifications. The results of the laboratory's control procedures, proficiency testing (required under subpart H) and assessment activities are used to verify test performance. However, as of April 24, 2003, laboratories must, before testing, either verify or establish performance specifications for any new test system.

Comment:

Some commenters expressed approval of the requirements for the establishment and verification of a test system's method performance specifications before its use, and maintaining records of this activity while the test system is used for patient testing.

Response:

We accept these positive comments and are retaining the requirements for the establishment and verification of method performance specifications formerly at § 493.1213 (now at § 493.1253). However, we realize the QC record retention requirements formerly at § 493.1221 may have been misinterpreted as permitting the laboratory to discard method performance specification records after a 2-year period even though the method may have continued to be used beyond this timeframe. Therefore, the analytic systems record retention requirement formerly at § 493.1221 (now at § 493.1105(a)(3)(i)) specifies that records of the laboratory's establishment and verification of method performance specifications must be retained for the period of time the test system is in use by the laboratory, but not less than 2 years. In addition, we are revising the original QC record retention requirement to accommodate the reorganization of the regulation and clarify its intent.

Comment:

A few commenters disagreed in general with the

requirements at § 493.1215, Equipment maintenance and function checks. Other commenters requested clarification. One commenter felt that the requirements were too stringent, and another offered specific language for revision. One commenter felt CMS, not the manufacturer, should establish the frequency for performing function checks.

Response:

Equipment maintenance and function checks are necessary to ensure accurate and reliable test performance. We are relocating the requirement formerly at § 493.1215 (now at § 493.1254) and renaming it Maintenance and function checks. Laboratories using unmodified manufacturers' equipment, instruments, or test systems must perform maintenance and function checks as defined by the manufacturer with at least the frequency specified by the manufacturer. Laboratories must also document maintenance and function checks performed. We are adding language at § 493.1254(a)(2) requiring that function checks be within the manufacturer's established limits before conducting patient testing. We are also retaining the present requirement (now at § 493.1254(b)) for laboratories to establish protocols that ensure proper test system performance, accurate and reliable test results and test reporting for equipment, instruments, or test systems developed in-house, commercially available but modified by the laboratory, or when protocols for maintenance and function checks are not provided by the manufacturer. In addition, laboratories must document the maintenance and function checks performed.

Under this final rule, we are not defining intervals for the performance of maintenance or function checks because the manufacturer is better able to define the appropriate procedures and intervals necessary to maintain and ensure proper equipment, instrument, and test system performance.

Comment:

Several commenters suggested that § 493.1217, calibration and calibration verification, or substantially equivalent requirements, should also apply to FDA-approved or cleared, unmodified moderate complexity testing at § 493.1202(c). In addition, we received comments requesting clarification of § 493.1217. One commenter stated that CMS, not the manufacturer, should establish the frequency of calibration. A manufacturer commented that a loose interpretation of the calibration verification requirement to assay calibration materials in the same manner as patient samples is needed for certain blood gas analytes because buffers and gases used to calibrate the instruments are not like patient samples and cannot be assayed in the same manner as patient samples.

Response:

We agree with the commenters and are specifying in this final rule that effective, April 24, 2003, calibration and calibration verification requirements (now at § 493.1255) will apply to all nonwaived testing.

To respond to the commenters' concerns that the calibration and calibration verification requirements are unclear, we are making some minor revisions in language for clarification purposes and removing duplicate requirements. For example, the definitions of calibration and calibration verification and reportable range are being slightly modified (now at § 493.2). We are also removing the requirement formerly at § 493.1217(b)(2)(ii)(B)(1) for laboratories to perform calibration verification using calibration materials appropriate for the methodology and, if possible, traceable to a reference method or reference material of known value to allow laboratories flexibility in choosing materials for calibration verification.

In addition, we are retaining the requirement for laboratories, at a minimum, to perform calibration and calibration verification procedures using the manufacturers' test system instructions and the criteria verified or established by the laboratory formerly at §§ 493.1217(b)(1) and 493.1217(b)(2) (now at §§ 493.1255(a)(1), 493.1255(a)(2), 493.1255(b)(1) and 493.1255(b)(2)). We are also retaining the requirement that calibration must be performed whenever calibration verification procedures are unacceptable and calibration verification be performed using a minimum of 3 values to verify the laboratory's reportable range, at least once every 6 months or whenever an event occurs as specified formerly at § 493.1217(b)(2)(ii)(C) (now at § 493.1255(b)(3)).

In response to the comment that the frequency of calibration be mandated by CMS, we are retaining the requirement formerly at § 493.1217(b)(1) (now at § 493.1255(a)) that requires laboratories to calibrate according to the manufacturer's instructions, if provided, and the laboratory's specifications. We believe that laboratories should perform calibration at the interval specified by the manufacturer to ensure proper instrument and test system performance. For calibration verification formerly at § 493.1217(b)(2) (now at § 493.1255(b)), laboratories are to follow the manufacturer's specifications and the laboratory's established protocols for calibration verification that must be performed at least once every 6 months. We believe this is the maximum interval allowable for verifying accuracy and stability. In addition, we are emphasizing that these regulations set forth minimal requirements. In establishing or verifying performance specifications as required at § 493.1253, the laboratory may find it necessary to calibrate or verify calibration more frequently or to use more calibration materials than required at § 493.1255.

In response to the comment concerning the inability of testing calibration materials (buffers and gases) in the same manner as patient specimens when verifying the calibration of blood gas assays, we are retaining the additional requirements for routine chemistry formerly at § 493.1245 (now at § 493.1267) that supersede the general calibration and calibration requirements at § 493.1255. Section 493.1267(a) specifically addresses calibration and calibration verification of blood gas analyses and states the laboratory must calibrate or verify calibration according to the manufacturer's specifications and with at least the frequency recommended by the manufacturer. As long as the laboratory follows the manufacturer's calibration and calibration verification instructions for the blood gas instrument, the CLIA requirements for calibration and calibration verification are met.

Comment:

We received many comments concerning various components of § 493.1218, Control procedures. Some commenters misread the CLIA regulation, and others offered specific language for revision. Most commenters opposed testing two levels of control material each day of use. One commenter indicated that the CLIA requirements are burdensome and will increase the cost of testing. Some commenters expressed concern that the requirements are arbitrary and do not recognize unit use test systems. Another commenter asked if procedural controls may be used to satisfy the control requirements.

Response:

We appreciate the commenters' concerns about the frequency and costs of performing control testing. However, CLIA regulations will continue to describe the purpose of control procedures, that is, to assess the accuracy and precision of test performance. The control procedures must monitor the complete analytical process by detecting immediate errors (those that occur due to test system failure, adverse environmental conditions or operator performance problems) and monitor over time the accuracy and precision of test performance that can be influenced by

subtle changes in test system performance, environmental conditions, and variance in operator performance (for example, different operators and same operator variations in specimen handling and testing).

In response to the comments concerning unit use test systems and the use of procedural controls, we are making allowances for the use of procedural controls in Appendix C of the State Operations Manual (CMS Pub. 7) when equivalent quality procedures can be demonstrated.

In addition, we are providing a definition for test system (now at § 493.2). A test system is the instructions and all of the instrumentation, equipment, reagents, and/or supplies needed to perform an assay or examination and generate test results.

A control material must detect errors in the entire testing process. It must also monitor the quality of the results provided by the test system. It may be supplied by the test system manufacturer or another source. We are also relocating the requirement for control materials to be tested in the same manner as patient samples formerly at § 493.1218(c) (now at § 493.1256(d)(8)) and clarifying that this requirement applies to control materials and that over time control testing must be rotated among all operators who perform the testing (now at § 493.1256(d)(7)).

We are reducing the frequency of testing control materials from “each run” to “each day of testing.” We are retaining the former requirements for qualitative procedures (test positive and negative control materials) and quantitative procedures (test two levels of control material). For test procedures producing graded or titered results, we are relocating the requirement to test a negative control and a control of graded or titered reactivity from Syphilis serology and General immunology formerly at §§ 493.1239(b) and 493.1241(a), respectively (now at § 493.1256(d)(3)(iii)).

As part of updating the requirements for new technology and test methodologies formerly at § 493.1218(b)(3) (now § 493.1256(d)(5)), we are revising the wording of the control requirement for electrophoresis procedures.

Comment:

One commenter urged that we remove specific stipulations for frequencies of performing QC or calibrations and substitute reference to an agency or professional association guidelines. The commenter also recommended that we accept alternate approaches suggested by a manufacturer as documented in test system instructions approved by the FDA. Another commenter suggested that § 493.1218(a) be revised to state, “that the laboratory should run controls as specified by the manufacturer's instructions.” Several commenters and one organization stated it is the laboratory director's responsibility to design the control system needed to achieve the desired quality.

Response:

We consider the requirements established in subpart K as the minimum control measures needed to ensure accurate and reliable test results. According to the requirements formerly at § 493.1213 (now at § 493.1253), each laboratory must verify or establish a test system's method performance specifications and use this information in determining appropriate calibration and control protocols. This may include more frequent testing and greater numbers of materials than specifically provided under CLIA regulations. For example, the laboratory is required to perform calibration and control procedures in the manner necessary to ensure quality results. In cases where the manufacturer's instructions require more stringent testing of calibrators, control materials, or both, the laboratory is required to follow the manufacturer's instructions. Therefore, we are clarifying that laboratories must follow the manufacturer's instructions for control testing if they meet or exceed the requirements now at § 493.1256(d)(3).

We agree with the comment concerning the laboratory director's responsibility to determine appropriate control procedures to monitor the complete analytical process. This requirement is specified in CLIA regulations under the director's responsibilities at § 493.1407(e)(5) for moderate complexity testing and § 493.1445(e)(5) for high complexity testing.

Comment:

A commenter suggested that acceptable control materials are two samples of different concentrations of controls or two concentrations of calibration material of a different lot other than the lot used for assay calibration, or any combination that results in both normal and abnormal values.

Response:

We agree with the commenter and emphasize that any calibrator used as control material must be of a different lot number than the one(s) used to establish a cutoff value or calibrate the assay. Therefore, we are revising this requirement formerly at § 493.1218(b)(2)(now at § 493.1256(d)(9)) to clarify that the calibrators used as control materials must be of different concentrations than the calibrators employed to set instrumentation. We recommend that the acceptable range of control materials reflect some clinical decision points, both normal and abnormal.

Comment:

One commenter suggested that § 493.1218(d) be revised to include a provision that if the performance specifications at § 493.1213 are exceeded, the laboratory must take corrective action before patient testing can continue.

Response:

We agree with the commenter. The requirements formerly at § 493.1219(a) (now at § 493.1282(b)(1)) require corrective action, and the requirements formerly at § 493.1701 (now at § 493.1289(b)) require the laboratory to review the effectiveness of its corrective actions and, if necessary, revise policies and procedures to prevent recurring problems.

Comment:

One commenter disagreed with the requirement to check each batch or shipment of media.

Response:

The CLIA regulations allow laboratories to use the manufacturer's QC checks of certain media, provided the manufacturer's product insert specifies that the manufacturer's QC checks meet the NCCLS standards for media QC formerly at § 493.1218(f)(4), now addressed in Appendix C of the State Operations Manual (CMS Pub. 7). For media not included by NCCLS, we believe it is critical that the laboratory check each batch of media to ensure that it is not contaminated, supports growth of appropriate organisms, and elicits the correct biochemical response(s). The former § 493.1218(f)(4) (now § 493.1256(e)(4)) clarifies that media checks must be performed before, or concurrent with, initial use of media.

Comment:

A few commenters expressed disagreement with the requirement to evaluate the detection phase of direct antigen systems and the extraction phase when it is included.

Response:

We believe the laboratory must verify that all steps of a testing procedure are functioning properly to prevent erroneous results. Therefore, we are retaining the requirement formerly at § 493.1218(b)(4) (now at § 493.1256(d)(3)(iv)) that requires laboratories to test two control materials, one that is capable of detecting errors in the extraction phase.

Comment:

One commenter agreed with requiring the determination of statistical parameters for each lot of calibration or control materials.

Response:

We are retaining the requirement formerly at § 493.1218(d)(2) (now at § 493.1256(d)(10)(i)) for laboratories to have statistical

parameters for each lot of control material. In addition, we are clarifying that the requirement applies to controls with quantitative results. When calibration materials (not used to establish a cutoff value or calibrate the test system) are used as control materials, the laboratory must have statistical parameters for each lot of calibration material.

Comment:

Some comments received were in reference to § 493.1219, Remedial actions. One commenter requested clarification and another requested deletion of § 493.1219(a)(2) that requires the laboratory to document all remedial action taken when patient test results are outside of the laboratory's reportable range for the test system. One individual asked for clarification of § 493.1219(d)(3) that requires the laboratory to maintain exact duplicates of both original and corrected reports for 2 years when errors in the reported test results are detected. One commenter suggested that no patient results that are less than the lowest calibrator or higher than the highest calibrator can be reported unless they are reported as less than or greater than the lowest or highest calibrator or the patient specimen is diluted to determine a higher value.

Response:

The requirement formerly at § 493.1219(a)(2) (now at § 493.1282(b)(1)(ii)) requires documentation of all remedial actions (now “corrective” actions) when patient values are outside of the laboratory's reportable range of patient test results. The documentation can be an instrument printout or other document that reflects the problem, corrective action, and outcome. The laboratories must retain this information for the required period and the corrective actions themselves may be as elementary as diluting and retesting the specimen. We are not making any revisions to this requirement.

The requirement formerly at § 493.1219(d)(3) (now at § 493.1105(a)(6)) requires the laboratory to maintain a copy of the original report, or be able to retrieve a copy of the original report and the corrected report for 2 years. Copies of test reports may be manually written, photocopies, electronically generated, or maintained on microfilm provided they contain all of the information supplied on the original test record or report.

We agree with the suggestion that results outside of the reportable range of the test system may not be reported without corrective action or explanatory remarks. Therefore, requirements formerly at § 493.1219 (now at § 493.1282, Corrective actions) require laboratories to have corrective action policies and procedures that are followed as necessary to maintain the laboratory's operation for testing patient specimens in a manner that ensures accurate and reliable patient test results and reports. This includes policies governing the reporting of patient results that exceed the reportable range of the test system. The analytic assessment requirements at § 493.1289 require the laboratory to monitor and evaluate the corrective actions taken and revise policies and procedures as necessary to prevent recurrences of problems.

Comment:

One commenter suggested that CLIA rules require all original worksheets and instrument printouts to be retained for 6 months, indicating that some laboratories destroy, delete, or erase records of unacceptable QC in order to avoid showing remedial action and reassessment of all patient tests results associated with the failure.

Response:

We understand the concerns expressed by the commenter. However, we believe the CLIA regulations adequately address documenting all control procedures performed formerly at § 493.1221 (now at §§ 493.1256(g) and 493.1105(a)(3)), maintaining records of all control procedures performed formerly at § 493.1221 (now § 493.1105(a)(3)), assessing corrective actions taken formerly at § 493.1705 (now at §§ 493.1289(a) and (b)) and retention of the original worksheets and instrument printouts for a period of 2 years or more formerly at § 493.1107 (now at § 493.1105(a)(3)). We also believe that if the laboratory deletes or alters a control result in any manner, it is expected that the laboratory will document the exact circumstances in which deletion or alteration occurred and document all corrective actions taken to prevent reoccurrence.

Comment:

One commenter felt that there should be a requirement that any abnormal, life-threatening, or panic value result obtained on a moderate complexity test should be repeated by a more accurate method of testing.

Response:

The requirement formerly at § 493.1109(f) (now at § 493.1251(b)(13)) requires laboratories to develop written procedures for reporting life-threatening results (panic or alert values). In addition, under the requirement formerly at § 493.1109(f) (now § 493.1291(g)) laboratories must immediately alert the individual or entity that requested the test and, if applicable, the individual responsible for using the test results when any test result indicates an imminently life-threatening condition. In addition, it is the responsibility of each laboratory to ensure that the results it reports are accurate. Repeat testing is one method of verifying the test results. However, it is up to each laboratory to determine the protocols it will follow to confirm the test results that it reports.

Section 493.1223 Condition: Quality Control-Specialties and Subspecialtes for Tests of Moderate or High Complexity, or Both

Specific comments received and response to comments regarding § 493.1223, specialty or subspecialty control requirements are set forth below.

Comment:

One commenter stated that the specialty and subspecialty QC requirements are too lenient.

Response:

The specialty and subspecialty QC requirements are minimum requirements that reflect good laboratory practice and must be followed by all laboratories performing nonwaived testing. However, based on the laboratory's establishment and verification of its test systems' performance specifications (now at § 493.1253), the laboratory may determine that, to ensure accurate and reliable test results, it must implement more stringent control procedures than the minimum requirements imposed. In addition, it is the laboratory director's responsibilities to ensure that the laboratory has systems that ensure the quality of the laboratory services provided and identify failures in quality as they occur (§§ 493.1407(e)(5) and 493.1445(e)(5)).

Comment:

One commenter disagreed with § 493.1223 stating a laboratory could lose approval to perform testing in an entire specialty or subspecialty if it is deficient in performing QC for a single test. The commenter urged that the language be changed to “Failure to satisfy requirements for an individual test or analyte would result in loss of approval for that test or analyte only.”

Response:

We emphasize that CLIA certification of laboratories is not granted on a test-by-test basis, but by specialty or subspecialty of testing. Therefore, if a laboratory has significant problems related to only one test or analyte in a specialty or subspecialty and the laboratory fails to correct those problems, it could jeopardize its certification for the specialty or subspecialty area. For example, the laboratory is notified in writing of the deficiencies found during a survey and is given an opportunity to correct the deficiencies. If the laboratory does not correct the deficiencies, sanctions could be imposed as specified in Subpart R—Enforcement Procedures. Therefore, we are deleting the enforcement

information formerly at § 493.1223 because subpart R contains this information. In addition, revocation of specialty or subspecialty certification for problems related to a particular test would be taken only as a last resort.

Sections 493.1225 Condition: Microbiology; 493.1227 Condition: Bacteriology; 493.1229 Condition: Mycobacteriology; 493.1231 Condition: Mycology; 493.1233 Condition: Parasitology; and 493.1235 Condition: Virology

Specific comments received and response to comments regarding §§ 493.1225, 493.1227, 493.1229, 493.1231, 493.1233, and 493.1235 are set forth below.

Comment:

A professional organization, the American Society for Microbiology (ASM), commented that the CLIA QC requirements should be revised over time as new information is made available about the performance parameters of reagents or test systems. At a CLIAC meeting, this organization presented data on control failures for commercial microbiology reagents and stains and suggested that the current frequencies for control testing of a number of microbiology tests or reagents are excessive. ASM collected the data via two surveys of 304 clinical microbiology laboratories that perform varying levels of microbiological testing. It included failure rates for a total of 14,731 lots of reagents and stains, representing 21 different tests. Reagents and stains for 11 of the tests surveyed currently have control testing frequencies specified in the CLIA regulations: catalase, oxidase, coagulase plasma,

Salmonella

antisera,

Shigella

antisera, Gram stain reagents, optochin, bacitracin, Cefinase

Tm

(beta lactamase), X and V factor strips and disks, and germ tube test. In this final rule, specific control testing frequencies are not given for eight reagents (spot indole, staphylococcal latex reagents, streptococcal latex grouping reagents, PYR disks, deoxycholate, KOH (fungal), LAP disks, and ALA) and two stains (lactophenol cotton blue and methylene blue). Based on the results of their surveys, the ASM proposed that laboratories should only be required to test new lot numbers of those commercial microbiology reagents that had a 98 percent or greater success rate (all reagents they surveyed met this requirement). In addition to testing each new lot, ASM recommended that laboratories test

Salmonella

and

Shigella

antisera every 6 months thereafter. ASM recommended that for epidemiological testing conducted in public health laboratories, the frequency for testing Salmonella and Shigella antisera should be determined by the periodicity supported by each laboratory's data.

In making this presentation, ASM stated that the changes they were proposing would improve the cost effectiveness of the CLIA program and quality assurance programs in clinical laboratories without compromising public health. The CLIAC supported the proposal and recommended the incorporation of these changes into the CLIA regulations.

Response:

We appreciate the efforts of ASM, and the data they provided. The survey results provided the supporting information and data needed to revise the control testing frequency requirements. Based on the low failure rates for the commercial microbiology reagents surveyed, we agree it is adequate to test the majority of these reagents with each batch (prepared in-house), lot number (commercially prepared), and shipment when prepared or opened for positive, negative, and graded reactivity, as applicable. We also agree with checking antisera initially and once every 6 months thereafter except for epidemiological testing that is not subject to CLIA.

For two of the stains surveyed, the Gram stain and methylene blue, we do not agree that the low failure rate of the reagents is sufficient reason to decrease the stringency of the control requirements. The Gram stain procedure uses several reagents and has multiple steps that require specific timing for accurate results. Also, interpretation of the stained smear requires individual skill and expertise. By decreasing the frequency of control testing for this procedure to once every batch, lot number, and shipment, small laboratories that perform only rare Gram stains on direct specimens may not test controls for a period of months. We do not believe this is appropriate for a critical test used, in some cases, to presumptively diagnose an infectious disease (for example, direct smear for

Neisseria gonorrhoeae

). For this reason, we are maintaining the current weekly control testing requirement for Gram stain in addition to testing with each new batch, lot number and shipment.

Similar to the Gram stain usage in small laboratories, methylene blue stains may not be performed for an extended period of time, especially in laboratories that do not routinely use this staining procedure. We do not believe it is overly burdensome to require control testing of this stain each day of use.

In making the revisions discussed above, we deleted the specific control requirements for the reagents surveyed by ASM in the subspecialties of bacteriology formerly at § 493.1227 (now at § 493.1261) and mycology formerly at § 493.1231 (now at § 493.1263), except for requiring in bacteriology that the Gram stain be tested each week of use, and antisera be tested when each batch, lot number, and shipment is prepared or opened, and once every 6 months thereafter. We are also requiring in mycology that the laboratory check each batch, lot number, and shipment of lactophenol cotton blue when prepared or opened for intended reactivity with control organisms. Additional control testing for lactophenol cotton blue is not required. The required control testing frequencies for other reagents and stains will default to the general control procedures requirements formerly at § 493.1218(f) (now at § 493.1256(e)(1) and (2)). The general control requirements for reagents include testing each batch (prepared in-house), lot number (commercially prepared) and shipment when prepared or opened. The general control requirements for stains (for example, methylene blue) include testing staining materials for intended reactivity each day of use. As indicated by ASM, we believe these changes will decrease the cost of microbiology testing, without significantly affecting the quality of the test results.

The CLIAC requested further input from ASM on appropriate control requirements for microbiology. ASM submitted the following recommendations based on consultation with clinical microbiologists:

• The mycology requirement (for auxanographic media for nitrate assimilation) to check the nitrate reagent each day of use with a peptone control is not relevant since most laboratories no longer perform this test for fungal identification. This requirement could be deleted, and if laboratories do use the procedure, it would be sufficient to perform control testing with each batch or lot.

• The requirement for parasitology laboratories to check permanent stains, each month of use, with a fecal sample should be changed to “with a fecal sample or commercial QC slide.”

• To control the decontamination process for mycobacteriology culture specimens, process a specimen containing

Mycobacterium fortuitum

with each new lot number or batch of decontaminating agent.

• The frequency of control testing should be standardized for all microbiology subspecialties. Although there has been no data collected for reagents or stains used in subspecialties

other than bacteriology, ASM suggested that it was their experience that these reagents and stains perform as well as the reagents surveyed for bacteriology.

• Molecular amplification control procedures should adhere to standards outlined in the NCCLS document “Molecular Diagnostic Methods for Infectious Diseases, MM3-A, 1995.” At a minimum, control procedures for these tests should validate cell lysis, absence of inhibitors, absence of contamination, and adequate amplification. The following controls should be included with each run:

• Positive control (low range of assay sensitivity).

• One to five negative controls.

• Internal control.

• Quantitative assays should include two to three standards of known copy number. For microbial genotyping, control procedures should include at least two isolates of the same species being tested. One isolate should have the same phenotype as the unknown, and one should be a different phenotype.

Response:

Our responses to the above recommendations are set forth below.

We agree that the mycology requirement for control testing of nitrate assimilation on auxanographic media is not relevant for the large majority of laboratories performing fungal identification, and have deleted that requirement. If laboratories use the procedure, they will be required, as stated formerly at § 493.1218(f) (now at § 493.1256(e)(1)) to test the medium and reagents with each batch (prepared in-house), lot number (commercially prepared), and shipment when prepared or opened. This will be the same control testing as required for other reagents and media used for fungal identification procedures.

The language formerly at § 493.1233(c) (now at § 493.1264(c)) requires laboratories to check permanent stains each month of use by using a fecal sample control. This terminology does not preclude the use of a fecal sample as a control or a commercially prepared control slide. The requirement remains as written in existing CLIA regulations; however, we will note this clarification in Appendix C of the State Operations Manual (CMS Pub. 7).

We recognize ASM's concern that the mycobacteriology decontamination process be monitored and adequately controlled to ensure that the decontaminating agent is of the proper strength to kill contaminating organisms without destroying mycobacteria (especially

Mycobacterium tuberculosis

). However, the method they suggested for doing this is only one way in which it may be accomplished. There are a number of other ways in which this process may be controlled (for example, monitoring the contamination rate over time to ensure the appropriate organisms are being killed). In an effort to maintain flexibility in CLIA regulations, in this final rule, we are not adding this ASM proposed control requirement to those for mycobacteriology. As noted formerly at § 493.1103(a) (now at § 493.1232), the laboratory must establish and follow written policies and procedures that assure optimum integrity of patient specimens from the time they are collected until testing has been completed and results reported. In addition, former § 493.1103(a) (now at § 493.1242(a)(6)) requires laboratories to have and follow written policies and procedures for specimen processing, and former § 493.1703 (now at §§ 493.1249(a) and (b)) requires the monitoring and assessment of these policies and procedures, and the implementation of corrective actions to resolve problems that are identified. These requirements ensure that the processing of mycobacterial specimens is monitored, assessed, and controlled, while allowing the laboratory to use any of several acceptable methods to do so.

We agree with ASM that, whenever possible, the frequency for control testing should be standardized for all microbiology subspecialties. Frequencies for individual reagents and stains are not specified in CLIA regulation for mycology and virology. For parasitology, a frequency requirement (to test once a month) is only given for permanent stains. The frequency requirement for all other reagents and stains in these subspecialties is the default contained in the general control procedure requirements that are now at § 493.1256(e)(1) and (2).

We agree appropriate requirements for molecular amplification procedures are needed, and that the NCCLS standards are an excellent reference for laboratories to use. Requirements addressing most of the recommendations made by ASM for amplification procedures are included in CLIA regulations, although not as specifically as suggested by this organization. CLIA regulations require the laboratory director to have control procedures to monitor the complete analytic process. For amplification procedures this includes, in general, validating cell lysis and ensuring absence of inhibitors, absence of contamination, and adequate amplification. The CLIA requirements for control procedures for all tests are now at § 493.1256(d). This provision requires all laboratories to follow manufacturer's instructions for control testing, and to, at minimum, conduct a test that includes two control materials of different concentrations (a positive and negative control are required for qualitative tests) on each day patient specimens are tested. CLIA regulations require that if the laboratory determines additional numbers or types of controls, or a greater frequency of running controls is needed to detect immediate error and monitor test performance over time, the numbers, types, and or frequency of controls must be increased accordingly.

While we agree with the recommendation made by ASM describing the positive and negative controls that should be used for molecular amplification procedures, the CLIA control requirements are minimum requirements and do not specify that a positive control must be at the low range of assay sensitivity, or that more than one negative control be tested daily. Likewise, these minimum requirements do not specify the types of controls that must be included with microbial genotyping, but only that two controls must be tested each day patient specimens are tested.

However, if test system instructions specify such control testing, or if the laboratory determines (during its initial evaluation of the test system at § 493.1253) that more controls are needed, the additional control testing must be performed.

For molecular amplification procedures, ASM also recommended the inclusion of an internal control in each run, primarily to detect inhibition of the amplification process. We agree that for some amplification procedures the presence of inhibitors or interfering substances in certain specimens may cause false negative test results, and that for these procedures, a control system is necessary to detect inhibition. However, as noted by NCCLS, inhibitors are not a significant source of false negative results for every test, and if inhibitors or interfering substances are encountered only rarely, NCCLS does not recommend running controls for inhibition. Therefore, we have added a requirement at § 493.1256(d)(3)(v) that states, if reaction inhibition is a significant source of false negative results, the laboratory must include a control system to detect such inhibition.

In response to the ASM recommendation that quantitative assays include two to three standards of known copy number, as stated above, under CLIA regulations, quantitative

tests must include at least two control materials of different concentrations per day. Standards may be used in lieu of control materials, as long as they are not the same as the materials used to calibrate the test system or establish a cutoff.

In reviewing the CLIA regulations concerning control procedures and QA requirements for molecular amplification procedures, the CLIAC discussed appropriate control procedures and QA for genetic testing (September 16, 1998 through September 17, 1998). CLIAC recommended that controls for genetic testing should be considered for laboratories in general, including ensuring that adequate controls are in place to minimize contamination. This is especially important when performing molecular amplification procedures. To ensure the control of contamination, we have amended the requirements for facilities, formerly at § 493.1204(a) (now at § 493.1101(a)) to require laboratories to be constructed, arranged, and maintained to minimize contamination of patient specimens, equipment, instruments, reagents, materials, and supplies. A uni-directional workflow must be maintained for molecular amplification procedures not contained in closed systems. This must include physically separate areas for specimen preparation, amplification and product detection and, as applicable, reagent preparation. We believe these measures will decrease the potential for contamination to the extent possible in a clinical laboratory.

Comment:

Several commenters requested clarification of the control requirements for kit systems used for bacterial and fungal identification. One commenter specifically requested the addition of a provision at § 493.1231, Mycology, that would require the testing of each new shipment of test kits or strips used for organism identification with organisms giving positive and negative reactions for each test before or concurrent with testing of clinical isolates. Another commenter questioned whether these systems would be subject to the requirement described at § 493.1202(c)(4) to test at least two levels of control materials each day of testing.

Response:

We agree with the commenter that in mycology, or any other subspecialty area of microbiology, new shipments of test kits or strips used for organism identification should be tested with organisms giving positive and negative reactions for each test before or concurrent with initial testing of clinical isolates. This includes identification kits or panels that are inoculated and read manually, and those that are part of an automated instrument system. We are retaining the requirement formerly at § 493.1218(f)(1) (now at § 493.1256(e)(1)) that laboratories check each batch (prepared in-house), lot number (commercially prepared), shipment of reagents, disks, stains, antisera, and identification systems (systems using two or more substrates and/or reagents) when prepared or opened for positive and negative reactivity. We do not believe additional testing of these systems is needed if they are stored and maintained under appropriate conditions. Further testing is only necessary if labile reagents must be prepared or used each time the kit is used or if specified by the manufacturer.

Comment:

Several commenters requested clarification of the control requirement at § 493.1218(b)(1) for qualitative tests as applied to microbiology procedures. The commenters asked which of the biochemical tests or media used for microbial identification would be considered qualitative tests.

Response:

Biochemical tests using specific reagents or growth tests that employ selective or differential media (for example, indole tests, citrate media) that are a part of the total system of identification from culture are not considered qualitative tests in microbiology. Therefore, we are retaining the requirement formerly at § 493.1218(f)(1) (now at § 493.1256(e)(1)) that states laboratories must check each new batch (prepared in-house), lot number (commercially prepared), and shipment when prepared or opened for positive, negative, and graded reactivity, if applicable. Specifically, former § 493.1218(f)(4) (now at § 493.1256(e)(1) and (4)) requires each batch of media to be checked before or concurrent with initial use for sterility, and its ability to support, select, or inhibit growth, as intended, and/or provide the appropriate biochemical response. The manufacturer's control checks of media may be used if the product insert specifies they meet the NCCLS standards for media control testing. These individual procedures do not require control checks with each run of patient specimens or further testing unless specified by the manufacturer or under specialty or subspecialty control requirements. Biochemical tests or media that provide microbial identification from a direct specimen or culture (for example, direct antigen tests for group A streptococcus, bacterial serotyping from culture) are considered qualitative microbiology tests and are graded for reactivity. We are retaining the control procedures requirements for qualitative test systems formerly at § 493.1218(b)(1) (now at § 493.1256(d)(3)(ii)).

Comment:

One commenter recommended we add “XV discs or strips” to § 493.1227(a)(2) that requires testing both positive and negative control organisms each week of use, and delete § 493.1227(b) that requires testing the XV discs or strips with only a positive control organism each week of use.

Response:

Testing of XV discs or strips was limited to only a positive control each week of use because there is no known available control to check negative reactivity for the group of organisms that this test identifies. We are deleting the specific QC requirements for testing X, V, and XV disks or strips. These disks or strips are now subject to the general control procedure requirements formerly at § 493.1218(f)(1) (now at § 493.1256(e)(1)) that include testing each new batch (prepared in-house), lot number (commercially prepared), and shipment when prepared or opened for positive and negative reactivity. Since there is no control available to check negative reactivity for XV disks or strips, the use of only a positive control for XV disks or strips will be deemed to meet the CLIA regulation as specified in Appendix C of the State Operations Manual (CMS Pub. 7).

Comment:

Several commenters recommended we change the control requirement for daily testing of antimicrobial susceptibility procedures to a weekly requirement, as specified by NCCLS. One commenter also suggested manufacturers develop control procedures consistent with NCCLS antimicrobial susceptibility testing standards whenever feasible.

Response:

CLIA requires daily control checks for antimicrobial susceptibility testing, formerly at § 493.1227(c)(2) (now at § 493.1261(b)(1)) unless CMS approves a procedure that provides equivalent quality testing as specified in Appendix C of the State Operations Manual (CMS Pub. 7). In this case, the procedure providing equivalent quality testing is the NCCLS standard allowing the laboratory to perform weekly control testing of antimicrobial susceptibility procedures after establishing accuracy control limits through initial daily testing. The laboratory may continue performing weekly control testing provided the control results do not exceed the established limits.

Comment:

One commenter requested clarification of the control requirements for antimicrobial susceptibility testing

with regard to the frequency of testing the disks, media, and overall procedure. The commenter felt that there is a contradiction between §§ 493.1227(c) and (c)(2) and that one of these statements should be deleted.

Response:

In the former regulation, antimicrobial susceptibility testing requires that whenever a new batch of media or a new lot number and shipment of antimicrobial agents (disks) are put into use, the laboratory must verify that the media and agents perform within acceptable control parameters for testing. Following this initial verification that the test components (that is, media and antimicrobial agents) are working appropriately, the test procedure must be checked routinely with appropriate control strains to ensure that it is being performed accurately and all components of the procedure continue to work properly. This routine control procedure must be performed each day of patient testing or can be performed weekly. The weekly QC testing will be deemed to meet CLIA requirements, if performed as specified in the approved procedure providing equivalent quality testing in Appendix C of the State Operations Manual (CMS Pub. 7). The control organisms must be within established control limits before patient results can be reported.

Although we did not intend for the requirements at §§ 493.1227(c) and (c)(2) to appear contradictory, we are revising the language now at § 493.1261(b) for clarification of these requirements. In addition, we are making conforming changes to the language pertaining to the requirements for antimycobacterial and antifungal susceptibility testing for consistency and to be current with testing performed in these subspecialties. These requirements, formerly at §§ 493.1229(d) and 493.1231(d), are now at §§ 493.1262(b) and 493.1263(b).

Comment:

A number of commenters stated the control requirements for identification procedures used in mycobacteriology at § 493.1229(a) should not selectively require positive and negative acid-fast control organisms to check the iron-uptake test each day of use while requiring only a positive acid-fast control for all other procedures. The commenters recommended that all identification procedures used in mycobacteriology be tested each day of use with an acid-fast organism that produces a positive result, and an acid-fast organism that produces a negative result.

Response:

We agree with these commenters and because the incidence of infection caused by a variety of mycobacteria is increasing significantly, it is important for laboratories to accurately identify individual species within this genus. This results in increasing numbers and types of identification procedures being performed and it is critical that the accuracy of each of these tests be verified each day of use. This can best be ensured each day of use by including both an acid-fast control organism that produces a positive reaction and an acid-fast control organism that produces a negative reaction for each test. We are revising the requirement formerly at § 493.1229(a) (now at § 493.1262(a)) to reflect this change.

Comment:

One commenter expressed concerns regarding the expense of testing controls and stated that the frequency for checking positive and negative reactivity of the BACTEC NAP test used to identify

M. tuberculosis

should be changed from each day of use to each week of use. This commenter suggested the requirement for testing a positive control each day of use could be satisfied by subculturing the growth from the BACTEC bottle to a solid media to detect appropriate colony and microscopic morphology.

Response:

The control requirements were written to address test complexity and specialties or subspecialties of testing, not specific test systems or procedures. Test-specific CLIA regulations are only developed when tests are not adequately addressed in the general or specialty or subspecialty requirements. The commenter requested a change in CLIA regulation because of the expense of performing controls each time the BACTEC NAP test is set up. The alternative method that the commenter suggests for a positive control is not actually a control on the ability of the NAP test to inhibit growth of

M. tuberculosis,

but is a confirmatory test for the presence of this organism.

Although we agree with confirming results of the NAP test, it is not the same as using positive and negative control organisms to check the NAP vials for their ability to inhibit growth of

M. tuberculosis

and to allow growth of other mycobacteria. However, we understand the financial concerns associated with running positive and negative controls each day of use for this test. Since the test has a growth control included as part of each test, and the manufacturer indicates the media is stable and does not recommend testing positive and negative organisms as frequently as each day of use, we agree with the commenter that laboratories should only be required to check positive and negative control organisms each week of use. In addition, we are specifying this requirement as provided at § 493.1256 as an alternative procedure in Appendix C of the State Operations Manual (CMS Pub. 7).

Comment:

One commenter stated positive and negative reactivity should be checked each day of use for all acid-fast staining procedures, rather than each week of use.

Response:

We agree with the commenter that both fluorochrome and conventional acid-fast stains should be tested more frequently than each week of use and that both positive and negative control organisms should be tested. Nonpathogenic mycobacteria in water supplies have been found to contaminate buffers, rinse water, or other reagents, producing false positive staining results. Given the widespread use of acid-fast stains with the increasing incidence of mycobacterial disease, it is critical that the accuracy of these tests be verified each day of use. Therefore, we are deleting the requirements formerly at §§ 493.1229(b) through 493.1229(c) for testing fluorochrome and conventional acid-fast stains each week of use. The requirement for testing conventional acid-fast stains will now default to the general control requirement for stains formerly at § 493.1218(f)(2) (now at § 493.1256(e)(2)) that requires testing staining materials for intended reactivity each day of use. For stains that provide positive and negative reactivity (intended reactivity), we are revising the language to clarify that stains must be tested with positive and negative controls each day of use. By eliminating the subspecialty requirement for fluorochrome acid-fast stains, the general control requirement for fluorescent stains formerly at § 493.1218(f)(3) (now at § 493.1256(e)(3)) becomes applicable to these procedures. This general requirement specifies testing for positive and negative reactivity each time of use. It is appropriate to require the same control testing for fluorochrome acid-fast stains as are required for all other fluorescent stains.

Comment:

One commenter recommended the deletion in bacteriology of testing positive and negative organisms each week of use for acid-fast stains as required in § 493.1227(a)(2) and replacement of the mycology term “acid-fast stain” at § 493.1231(c), with “modified acid-fast stain.” This commenter emphasized that acid-fast stains are used in mycobacteriology rather than bacteriology, and that the procedure for staining used in mycology is a modification of the acid-fast stains performed in mycobacteriology.

Response:

We agree with this commenter on both of these points. Although acid-fast stains are occasionally performed in bacteriology, by deleting the requirement in bacteriology for testing acid-fast stains each week of use, it defaults to the general requirement formerly at § 493.1218(f)(2) (now at § 493.1256(e)(2)) that requires laboratories to test staining materials for their intended reactivity (including positive and negative reactivity, as appropriate) each day of use. We agree with the commenter that the staining procedure in mycology is a modification of acid-fast stain used in mycobacteriology; therefore, we are deleting the requirement formerly at § 493.1231(c) for performing control testing each week of use for (modified) acid-fast stains. Again, this results in the control requirement for these stains defaulting to the general requirement for testing each day of use and is reasonable based on the fact that we are now requiring positive and negative controls for all acid-fast stains each day of use.

Comment:

One commenter stated that the control regulation for mycology and mycobacteriology should require the use of a safety cabinet when testing in these specialty areas.

Response:

We agree with the commenter that safety is an important factor in laboratory testing, formerly at § 493.1204(b) (now at § 493.1101(d)) and laboratories are required to maintain a safe testing environment. Safety precautions must be established and observed to ensure protection from biohazardous materials. Under §§ 493.1445(e)(2) and 493.1407(e)(2), the laboratory director is responsible for ensuring a safe environment is provided for employees conducting non-waived testing. In addition, other government agencies enforce State and local laws and other Federal standards that ensure protection of employees and the public from biohazardous materials. These agencies include the Occupational Safety and Health Administration and the Environmental Protection Agency.

Comment:

One commenter stated that the wording at § 493.1235(c) is inappropriate. The commenter recommended the replacement of the word “culture” (referring to uninoculated controls) with “incubate” or “hold.” This individual stated that the use of the term culture as specified at § 493.1235(c) generally means to inoculate and inspect for growth.

Response:

We agree with this commenter and are replacing the term “culture” with the term “incubate” formerly at § 493.1235(c) (now at § 493.1265).

Comment:

A commenter requested clarification of the control requirements for virology as they pertain to direct antigen detection. This commenter recommended the addition of a statement to § 493.1235 following paragraph (c) that would read “The above QC requirements are not applicable to virology testing performed using direct antigen detection methods.”

Response:

We agree with the commenter that the wording formerly at § 493.1235(c) needs clarification. There are several types of tests that identify viruses, but this requirement only applies to cell culture methodologies used to isolate and identify viruses. Therefore, we are changing the language for this requirement, now at § 493.1265(a), to make it specific to cell culture methodologies.

Sections 493.1237 Condition: Diagnostic Immunology; 493.1239 Condition: Syphilis Serology; and 493.1241 Condition: General Immunology

Specific comments received and response to comments regarding §§ 493.1237, 493.1239, and 493.1241 are set forth below.

Comment:

A commenter stated § 493.1239(e) and § 493.1241(d), which refer to facilities manufacturing blood and blood products, should be deleted. This individual believes CLIA regulations should not cover manufacturing requirements.

Response:

We disagree with the commenter. These requirements refer to testing requirements under CLIA regulations (donor specimens) regardless of where the testing is performed. However, we are moving these requirements, formerly under the subspecialties of syphilis serology and general immunology, and placing them with other requirements addressing the immunohematological collection, processing, dating, labeling, testing, and distribution of blood and blood products now at § 493.1271, Immunohematology (formerly at § 493.1273(a)).

Comment:

One commenter requested clarification of the QC requirements for serological testing (both syphilis serology and general immunology) to run patient specimens concurrently with a positive serum control of known titer or controls of graded reactivity, if applicable, and a negative control. Specifically, this commenter questioned if these requirements refer to the additional controls run on a new kit to verify reproducibility, or if they pertain to the daily testing of the positive controls supplied in commercial kits. Other commenters objected to including two control materials each time patient testing is performed. One commenter thought only a positive control was necessary for immunology tests if the patient results were negative.

Response:

We agree with the commenters who objected to the syphilis serology and routine immunology requirements requiring two control materials each time patient testing is performed. With the development of more accurate and stable test systems, the requirements formerly at § 493.1239(b) and § 493.1241(a) for assaying controls concurrently with patient specimens are excessive for many of the test systems. We are, therefore, deleting these requirements. Laboratories performing these tests will now need to meet the applicable control procedures at § 493.1256. In addition, the laboratory must meet the requirements that pertain to establishing or verifying a test system's performance specifications before putting a new test system into routine use formerly at § 493.1213 (now at § 493.1253).

We disagree with the comment that testing only a positive control is sufficient if the patient results are negative. Laboratories, at a minimum, must follow the manufacturer's instructions and for qualitative tests, assay a positive and negative control each day of patient testing (now at § 493.1256(d)(3)(ii)). For procedures producing graded or titered results, a control material with graded or titered reactivity, as applicable, and a negative control material must be assayed each day testing is performed formerly at §§ 493.1239(b) and 493.1241(a) (now at § 493.1256(d)(3)(iii)). The control material supplied in commercial kits (test systems) may be used to meet the requirements formerly at §§ 493.1239(b) and 493.1241(a) (now at § 493.1256(d)(3)(iii)) providing the material is of known reactivity (titered or graded, as applicable) and is not the same material used to establish a cutoff or calibrate the test system if calibration of the test system is required (now at 493.1256(d)(9)).

Section 493.1245 Condition: Routine Chemistry

Specific comments received and response to comments regarding § 493.1245 are set forth below.

Comment:

One commenter expressed concern that §§ 493.1245(c) and (d) could be interpreted to mean that the same material could be used to calibrate the instrument and verify or control the test run for blood gas analyzers. The commenter stated that this would not

detect problems arising from deteriorated or contaminated calibrating solutions. The commenter also recommended the reference to calibrators be deleted from these sections and that control testing be performed using only control material.

Response:

We agree with this commenter. It was never our intent to infer by the wording of these requirements that calibration material used to calibrate a test system could be used as a control to monitor the test system's performance. However, we allow the use of calibration material as a control material provided it is from a different lot number than that used to calibrate the test system or establish a cut-off. Therefore, we are clarifying the use of calibration materials as control materials (now at § 493.1256(d)(9)), and eliminating the terms “calibration” and “calibration material” from the blood gas analysis requirements (now at § 493.1267).

Comment:

One commenter stated testing one sample of blood gas control per 8 hours of patient testing is not sufficient and is inconsistent with the general requirement for quantitative tests at § 493.1218(b)(2) that requires two controls of different concentrations with each run of patient specimens. This commenter recommended that at least two levels of control be required every 8 hour shift.

Response:

We revised the general control requirement formerly at § 493.1218(b) (now at § 493.1256(d)). The requirement now specifies, at a minimum, assaying two levels of control materials each day patient specimens are tested. We are deleting the term “run” from the regulation. Also, laboratories must perform control testing using the number and frequency specified by the manufacturer or established by the laboratory when those frequencies meet or exceed the minimum requirement. Therefore, the minimum control requirement for quantitative tests, unless a more frequent interval is recommended by the test system's manufacturer or the laboratory, is two control materials of different concentrations each day patient specimens are tested.

The requirement for one control material per 8 hours for blood gas analyses, formerly at § 493.1245 (now at § 493.1267) exceeds these general QC requirements. The blood gas control requirements also require the laboratory to use a combination of control materials that check low and high values each day of testing. In addition, for blood gas instruments that do not internally verify calibration at least every 30 minutes, the laboratory must include one sample of control material each time patient samples are tested. This final rule provides minimum requirements. Based on the laboratory's verification of the test system's performance specifications before routine patient use (now at § 493.1253) and establishment of its control procedures (now at § 493.1256(d)), the laboratory may determine that it needs to run additional control materials or run control materials at a more frequent interval to assure accurate and reliable test results.

Section 493.1249 Condition: Toxicology

Specific comments received and response to comments regarding § 493.1249 are set forth below.

Comment:

One commenter asked that the term “drug abuse screening using thin layer chromatography” at § 493.1249, Toxicology be modified to read “drugs-of-abuse screening using thin layer chromatography” (“drugs-of-abuse” is defined by the National Institute for Drugs of Abuse now National Substance Abuse and Mental Services Health Administration Laboratory Certification Program). This commenter also requested deletion of the requirement under § 493.1249(b) for at least one control sample to be processed and included in each chamber, stating that all environmental, chemical and material variables within a chamber are visualized by running calibration materials. The commenter added that controls should be analyzed with each run, and that each run should not exceed a 24 hour period.

Response:

We agree with the commenter that the control requirements formerly at § 493.1249 are not clear; therefore, we are revising the language to clarify the requirements. We are moving the requirements for thin layer chromatography to § 493.1256(d)(4) under Control procedures. In addition, we are revising the term “drug abuse screening” to read “all known substances or drug groups” identified and reported by the laboratory, to accommodate the wider use of the technology. However, we disagree with the commenter's statement that analyzing one control material per 24 hours is sufficient. If extractions and tests are performed more frequently than once per 24 hours, each “plate” or “card” (formerly referred to as “chamber”) must be spotted with at least one sample of control material to ensure that appropriate separation, and as applicable, extraction took place. The inclusion of a calibration material containing all known substances or drug groups reported by the laboratory using thin layer chromatography on each plate or card ensures appropriate identification of the substances or drugs in patient specimens.

Section 493.1253 Condition: Hematology

Specific comments received and response to comments regarding § 493.1253 are set forth below.

Comment:

We received several comments requesting the deletion of QC requirements in hematology because they would increase laboratory costs.

Response:

We agree with the commenters that the requirement to include two levels of control material each 8 hours of testing for automated hematology analyzers (for example, cell counters and differential counters) is somewhat excessive in light of the proven stability and reliability of these instruments. Therefore, we are deleting the specialty-specific control requirement for automated hematology analyzers formerly at § 493.1253(b), and are requiring laboratories to meet the general control requirements (now at § 493.1256(d)) when using automated hematology analyzers. However, the manufacturer's instructions and the laboratory's evaluation of the instruments' stability, environmental effects, and operator variance will determine the actual number, type, and frequency of testing control materials. At a minimum, the laboratories will have to test two control materials of different concentrations each day.

Comment:

One commenter requested that we remove the requirement for duplicative testing of patient and control specimens for manual coagulation tests, as required at § 493.1253(d)(2), since proficiency testing requirements do not allow for duplicative testing.

Response:

We disagree with the commenter and are retaining the requirement for duplicative testing of patient specimens and control materials for manual coagulation testing (now at § 493.1269(c)(2)). CLIA regulations for proficiency testing (PT) (§ 493.801(b)(2)) require the laboratory to test PT samples the same number of times that it routinely tests patients' samples. Therefore, since patient specimens must be routinely tested in duplicate, PT samples for manual coagulation testing must also be tested in duplicate.

Section 493.1257 Condition: Cytology and Section 493.1259 Condition: Histopathology

Approximately 66 percent of the 1,030 comments received concerning the final rule with comment period,

subpart K, were in response to the cytology requirements. The comments were primarily from professional organizations, cytotechnologists, pathologists, and other physicians. The major issues that commenters addressed include—

(1) Workload limits; (2) review of reactive reparative cases by a technical supervisor; (3) the 10 percent rescreen of negative cases screened by a cytotechnologist; and (4) the 5-year retrospective review of negative smears from patients with a current high grade lesion.

Specific comments and response to comments regarding §§ 493.1257 and 493.1259 are set forth below.

Comment:

Several commenters stated the language “non automated microscopic technique” used to describe the slides that are counted in the workload limit is inappropriate and might be confused with slides that are screened using a motorized mechanical stage or with slides that are read by an automated instrument.

Response:

We agree with the commenters and are removing the wording “non automated microscopic technique.” We also want to emphasize that slides that are read with a human component must be included in the 100 slide limit; slides that are read by an automated instrument that do not require human review are not included in the workload limit.

Comment:

A number of commenters and one cytology organization were opposed to establishing the workload limit at 100 slides examined in a 24 hour period. A few commenters felt the workload limit was too restrictive, while other commenters and the cytology organization indicated the limit was too high.

Response:

The CLIA statute at section 353(f)(4)(B)(i) specifically states that the standards must establish “the maximum number of cytology slides that any individual may screen in a 24 hour period.” Limiting the number of slides that may be examined in 24 hours to no more than 100 is the absolute maximum workload limit for an individual. However, we agree with the commenters that this may not be an appropriate workload for all individuals. To clarify our position, formerly at § 493.1257(b)(1) (now at § 493.1274(d)(2)), we specify that the Federal workload limit was not to be used as a performance target for cytology personnel. In addition, we specified formerly at § 493.1257(c)(4) (now at § 493.1274(d)(1)) that the cytology technical supervisor must establish a workload limit (not to exceed 100 slides examined per 24 hours) for each person examining slides and that at least every 6 months, the technical supervisor must re-evaluate and adjust, if necessary, each individual's workload limit. In addition, we are emphasizing that the workload limit applies only to individuals and does not apply to automated slide examination systems that may be used to screen slides and identify those smears requiring no human microscopic examination.

Comment:

One organization asked whether the workload requirements are applicable to technical supervisors or only to cytotechnologists. Several commenters suggested the workload requirement only applies to cytotechnologists.

Response:

The workload requirements apply to any individual who performs primary screening of cytology slides. This may be a technical supervisor or a cytotechnologist. We are also clarifying that while tissue pathology slides and previously examined gynecologic and nongynecologic slides are not included in the 100-slide workload limit for technical supervisors, the technical supervisor must subtract the time spent evaluating these slides and the time spent on any nonscreening duties from the time spent screening slides to appropriately adjust the workload.

Comment:

Many commenters and the cytology professional organizations opposed the workload provision to count as one-half slide those smears made using automated, semiautomated, or other liquid-based slide preparatory techniques that result in cell dispersion over one-half or less of the slide. Some commenters indicated that this workload limit should apply only to nongynecologic preparations, while others thought it premature to use this calculation for any cytologic preparations until sufficient scientific studies have been completed to document the establishment of a workload limit appropriate for these preparatory techniques.

Response:

In order to address concerns of the commenters, we are making several clarifications. First, the 200-slide workload limit was initially established in the February 28, 1992 final rule with comment period published in the

Federal Register

(57 FR 7002) in response to innovations in cytology preparatory techniques and acknowledgment that slide preparations that only occupy a portion of the slide will not count as a whole slide. Slide preparations (gynecologic and nongynecologic) made using automated, semi-automated, or other liquid-based preparatory techniques that result in a specimen that only occupies a small portion of the slide, are counted as one-half slide. Second, on January 19, 1993, we published a final rule with comment period in the

Federal Register

(57 FR 5212) removing gynecologic preparations. On July 22, 1993, we published a technical correction notice in the

Federal Register

(58 FR 39154) that inadvertently reinserted gynecologic preparations. In addition, Cytyc, manufacturer of ThinPrep

TM

, agrees that a 200-slide workload limit is too high for gynecologic preparations and has requested that the 200 slide workload limit not be applicable to gynecologic slides. We agree with the commenters and Cytyc corporation, and we are eliminating gynecologic slides from the 200-slide workload limit (now at § 493.1274(d)(2)(iii)). The 200-slide workload limit will only apply to nongynecologic slides.

Comment:

Many Commenters and the Cytology organizations agreed that a workload limit was appropriate for gynecologic preparations. However, they were opposed to establishing a workload limit for nongynecologic smears because these preparations vary greatly in specimen type or source, preparatory techniques, and cellularity requiring various time frames for evaluation. The commenters acknowledged the difficulty in establishing a workload limit for individuals who examine nongynecologic preparations exclusively or a combination of gynecologic and nongynecologic smears. For fine needl

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