Medical Device Link.

Originally Published IVD Technology March 2005

Regulations & Standards

Michelle B. Bandy is a regulatory affairs specialist at BD Diagnostic Systems (Sparks, MD). She can be reached at michelle_bandy@bd.com.

The Clinical Laboratory Improvement Amendments of 1988 (CLIA) apply to all laboratories that examine human specimens for diagnosing, treating, or preventing disease. Regardless of whether payment is received from Medicare or Medicaid for performing such tests, all labs are required to have a current and valid CLIA certificate to test human specimens.¹ The requirements for quality control (QC) testing have historically been defined by the CLIA test complexity categorizations: high complexity, moderate complexity, or waived. These categorizations are assigned based on complexity scores associated with the amount of knowledge, training, and interpretation required to perform the test.²

In January 2003, the final rule for 42 CFR Part 493 (68 FR:3640) was published, which consequently revised the prior laboratory requirements issued pursuant to CLIA. (This rule became effective in April 2003.) Before the 2003 final rule, labs were required to comply with the regulations in the 1992 final rule (57 FR:7002). According to this previous CLIA rule, laboratories performing high-complexity tests were required to meet all applicable standards of 42 CFR 493 subpart K. Moderate- complexity tests, if conducted using the methods cleared by FDA, were required to meet a subset of the standards in subpart K that included the following: complying with the FDA-cleared manufacturer’s instructions, maintaining a procedure manual, documenting remedial actions, and documenting the performance of calibration at least once every six months, control procedures using at least two levels of control materials each day of testing, and specialty and subspecialty procedures.³

Alternatively, laboratories performing moderate- and/or high-complexity tests could meet the QC requirements in the 1992 CLIA rule by following the product labeling. This was possible only if the IVD manufacturer’s instructions were cleared by FDA and deemed as meeting the CLIA requirements for general QC. Labs opting to use the product labeling to comply with CLIA QC requirements were also responsible for complying with any requirements in subpart K that were not addressed by the manufacturer’s instructions.³

Interpretive Guidelines for 2003 CLIA Regulations

The 2003 CLIA rule no longer differentiates laboratory QC requirements based on the complexity of the tests being performed. In this rule, QC requirements are the same for both moderate- and high-complexity tests, which are now defined collectively as non-waived tests.1 To provide guidance on the conditions for maintaining certification under the CLIA 2003 rule, the Centers for Medicare and Medicaid Services (CMS; Baltimore) published interpretive guidelines for labs.⁴

CMS developed these interpretive guidelines to assist CLIA surveyors and laboratorians in their efforts to comply with the CLIA requirements.⁵ The QC options presented in the guidelines are based on the QC mechanisms available in test systems.

Most laboratory tests are monitored for QC through two mechanisms: internal/procedural controls or external controls. Internal/procedural controls are designed into a test system to monitor one or more components for errors. Factors affecting a test system’s performance include elements of the analytical process (e.g., reagent function), operator variance (e.g., sample processing and handling), and environmental factors (e.g., variations in room temperature, humidity).⁴ An example of an internal control is a mechanism that prevents the report of a test result when the operating temperature falls outside of the acceptable range.

External controls are not designed into a test system. Instead, they are materials in a matrix similar to patient samples with expected properties. External controls are tested throughout all analytic test phases in the same manner as patient specimens, and therefore have the potential to monitor all the analytical components of a test system. Materials that may be used as external controls include commercially prepared or in-house prepared samples, proficiency test samples with confirmed results, reference or control organism strains, calibration materials (other than those lots used to calibrate the system), and previously tested patient specimens with established values.⁶

Laboratories may comply with the QC requirements outlined in the CLIA 2003 final rule (Sect. 493.1256) by conducting one of the following three methods: traditional QC, equivalent quality control (EQC), or QC procedures recommended by the IVD manufacturers if they meet or exceed the requirements specified for traditional QC.⁴

Traditional Quality Control

Traditional QC requires the most frequent QC testing. To comply with traditional QC requirements, laboratories must perform two levels of external control testing each day patient specimens are assayed. In addition, external QC testing must be rotated among all operators performing the test.4 The levels of external controls are based on the type of test (e.g., qualitative tests require a negative and positive control). Labs must also perform QC testing when the reagents are completely changed, major preventive maintenance is performed (e.g., a test system must be sent to the IVD manufacturer for repair), and any critical parts that may influence the test performance are changed.^4,7

Equivalent Quality Control

The interpretive guidelines outline three EQC options that offer alternatives to traditional QC and allow for less-frequent QC testing. Laboratories can implement an EQC option only after successfully performing the internal and external controls with a test system during a defined number of consecutive days. While the guidelines define the requirements for traditional QC and the EQC options, they also recognize the importance of following an IVD manufacturer’s recommendations for QC testing.

Based on the ability of a test’s QC mechanisms to monitor the analytical test process, it may be eligible for one of the three EQC options. The EQC option selected for a test is based on the presence or absence of internal/procedural controls and the functions of these controls.

Tests eligible for option 1 contain internal controls that monitor all analytical components of the test. Such eligible test systems require a documented EQC evaluation of the QC results for the system’s internal controls and two external control materials during 10 consecutive days of testing. Under option 1, a laboratory may reduce the frequency of QC testing of the external control materials to once per calendar month if the following criteria are met: the internal and external control results are acceptable during the 10 consecutive days, no issues are identified as a result of the ongoing quality assessments of the lab test, proficiency test results are acceptable, and laboratory personnel competency evaluations are acceptable.⁸

Tests eligible for option 2 contain internal controls that monitor only a portion of the test’s analytical components. Such eligible test systems also require a documented EQC evaluation of the QC results, but during 30 consecutive days of testing. In addition, under option 2, a laboratory may reduce the frequency of QC testing to once per calendar week if the criteria stated above are met, with the exception that the internal and external control results must be acceptable during the 30 consecutive days.⁸

Tests eligible for option 3 contain no internal controls. Such eligible test systems require a documented EQC evaluation of the test results for two levels of external control materials during 60 consecutive days of testing. Under option 3, a laboratory may also reduce the frequency of testing to once per calendar week if the criteria stated above are met, with the exception that the results for the external controls must be acceptable during the 60 consecutive days.⁸

If, either during an EQC evaluation or after implementing an EQC option, (reduced QC testing frequency), a control failure occurs, a laboratory must repeat the unacceptable control results. If the repeat control results are acceptable, no further corrective actions are required, and a lab may resume the evaluation process or the reduced external QC testing frequency. However, if the repeat control results are not acceptable, a lab must restart and successfully complete the EQC evaluation process prior to reimplementing an EQC option.

If a test has specialty or subspecialty requirements (i.e., Sect. 493.1261 through 493.1265, Sect. 493.1271 through 493.1278), the corresponding QC requirements are outlined specifically for that test, and therefore it is not eligible for EQC. Other tests that are not eligible for EQC include molecular amplification procedures, thin-layer chromatography, electrophoretic procedures, reagents, and media. Reagents and media have specific QC requirements defined in Sect. 493.1256(e).⁴

Certain tests have limited EQC eligibility. For example, tests that require an extraction procedure are only eligible for EQC options 1 and 2. While routine chemistry and hematology tests do have specialty requirements (i.e., Sect. 493.1267 through 493.1269), some may be eligible for EQC options 1 or 2.⁴

In addition, according to the interpretive guidelines, under no circumstances may a laboratory reduce the frequency of external control materials testing to less than what is recommended in an IVD manufacturer’s package insert or test system instructions. If EQC testing frequency is less stringent than the QC recommended by the manufacturer, the user must comply with the manufacturer’s recommendations.

Implementing the 2003 CLIA Rule

To assist laboratories with their implementation of the QC requirements in the 2003 CLIA rule, CMS is taking an educational approach during the current 2004–2005 inspection cycle.⁹ Each lab inspected by CMS will undergo one educational survey during the two-year period.⁶ This will give laboratories, inspectors, and the industry time to understand the requirements and implement measures to ensure compliance. CMS inspectors conducting the surveys will not generate deficiency statements for noncompliances to the 2003 CLIA rule. Instead, labs will be sent a letter describing the noncompliances noted in the surveys.⁶ However, any nonconformances to preexisting provisions from the 1992 CLIA regulation will be cited in a deficiency statement.

For many test systems, the required frequency of testing external controls has increased as a result of the 2003 CLIA rule. During the public comment period for this rule, CMS and the Centers for Disease Control and Prevention (CDC; Atlanta) received comments on this matter from state agencies, proficiency test programs, professional organizations, the Clinical Laboratory Improvement Advisory Committee (CLIAC), labs, physicians, and the general public. The commenters were concerned that the new testing-frequency requirements were overly burdensome, cost prohibitive, and arbitrary. While these concerns were recognized, CMS and CDC maintained that QC procedures are essential to ensuring the accuracy of patient test results in the varying environmental conditions and among varying operators. The agencies also believe that the costs for increased frequency of QC testing may decrease the long-term costs of retesting as well as unnecessary patient procedures and treatments.¹

Considerations for the IVD Industry

Laboratory directors are responsible for identifying the QC requirements for the nonwaived tests conducted in their labs. This process requires careful consideration of the capabilities of laboratory personnel, potential sources of errors of test systems, and costs of conducting QC testing. Lab directors may perceive evaluating each test against the new QC requirements as an onerous task. While the ultimate responsibility for CLIA compliance rests with the directors, IVD manufacturers can assist them by providing timely, test-specific information and relevant technical support. By providing such support, IVD companies have an opportunity to increase customer satisfaction and loyalty.

IVD manufacturers should be prepared to meet a laboratory’s emerging needs for test-specific technical information that is required to comply with CLIA. Manufacturers can appropriately plan for the type and level of support that is useful to their customers in ensuring the accuracy of patient test results. Such planning can be streamlined by understanding the lab directors’ needs.

For example, laboratory directors may request a test system’s sources of error to assist in determining the type of QC that must be implemented in their labs and incorporated in their procedure manuals. For test systems with no internal controls, the lab directors may request written documentation of the test system’s ability to maintain stable performance specifications over time. Reviewing the sources of error and a test system’s stability can help identify the components of the analytical process that need to be monitored. Directors can use this information to select the most appropriate QC option for their laboratory’s environment and operator variance. IVD manufacturers may create supporting documentation for their test systems that provide such information, along with explanations and recommendations for additional monitoring.

Laboratories that implement EQC instead of traditional QC will require a description of the test system and how it is categorized (e.g., qualitative, quantitative, specialty, etc.). By providing documentation on the test system’s capabilities, including the identification of which test components are monitored by internal controls, laboratory directors can select the QC option that best meets the needs of their facilities, and include their rationale for the selected option in their procedure manuals.

As described in the interpretive guidelines, external controls monitor all analytical phases of testing (i.e., test system components, environmental conditions, operator variance). IVD manufacturers should recommend sources of external controls to ensure that laboratories are testing materials that are compatible with the test system. This will prevent unnecessary user QC failures and the loss of time due to investigations and documentation of corrective actions. In addition, providing recommendations for sources of external controls can save labs the time and resources required to identify such external control materials.

While the 2003 CLIA rule provides an opportunity for the IVD industry to assist laboratories in their compliance with the new QC requirements, it has also created additional long-term challenges for the industry. As a result of the new QC requirements, labs may begin to seek out test systems that are designed to rely less on external controls and more on comprehensive internal controls to monitor their systems. Test systems with a simplified workflow may reduce potential sources of error and ultimately decrease the laboratory’s QC burden.

At the initial test development phase, IVD manufacturers should also consider the CLIA QC requirements as an important part of their design input criteria. Tests that are eligible for EQC option 1 will be most desirable to laboratories since they will require less-frequent QC testing and cost less for the labs to run. Manufacturers that implement innovative built-in QC measures into their test systems and provide test-specific technical support with documentation will be in a favorable position when marketing their products to laboratories performing nonwaived tests.

Conclusion

As the IVD industry, laboratories, and inspectors continue to understand, interpret, and implement the 2003 CLIA requirements, more questions and issues will likely arise. Many tests are available that examine human patient specimens for diagnosing, treating, and preventing disease. Each test has different capabilities, performance characteristics, procedures, and technologies.

Technological advances are permitting IVD companies to design and manufacture products that may require alternative QC options other than those currently provided in the interpretive guidelines. CMS has expressed its openness to identifying such alternative options. Because CMS recognizes the expertise of IVD manufacturers, the IVD industry has an opportunity to propose other QC options that would be appropriate for their assays and technologies. Such proposed options could provide more available QC testing options for labs, and, as such, offer them increased flexibility in their approaches to complying with the CLIA requirements.

References

1. Federal Register, 68 FR:3640, January 24, 2003.

2. “ Information on CLIA Waivers,” AMDM News 14, no. 3 (Winter 2002/2003).

3. Federal Register, 57 FR:7002, February 28, 1992.

4. “Appendix C of the States Operations Manual: Regulations and Interpretive Guidelines for Laboratories and Laboratory Services,” the Centers for Medicare and Medicaid Services Web site (Baltimore: 2004 [accessed 28 January 2004]); available from Internet: www.cms.hhs.gov/clia/appendc.asp.

5. “CLIA Guidelines to Offer New QC Options for Labs,” AACC Clinical Laboratory News 29, no. 12 (2003).

6. J Yost, “Final CLIA Quality System Regulation and Guideline Overview” (paper presented at the CLIAC Meeting, Atlanta, February 11–12, 2004).

7. “Clinical Laboratory Improvement Amendments (CLIA)—Updated Regulations Brochure #1,” the Centers for Medicare & Medicaid Services Web site (Baltimore: 2003 [accessed 27 January 2005]); available from Internet: www.cms.hhs.gov/clia/6603bk.pdf.

8. “Clinical Laboratory Improvement Amendments (CLIA)—Equivalent Quality Control Procedures Brochure #4,” the Centers for Medicare and Medicaid Services Web site (Baltimore: 2003 [accessed 27 January 2005]); available from Internet: www.cms.hhs.gov/clia/6606bk.pdf.

9. “Clinical Laboratory Improvement Amendments (CLIA) Policy and Data Reporting Guidance for First Survey Cycle Following Effective Date of CMS-2226-F,” the Centers for Medicare and Medicaid Services Web site (Baltimore: 2004 [accessed 27 January 2005]; available from Internet: www.cms.hhs.gov/clia/sc0416.pdf.

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