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2009-07_02-01

Quality Control in the Clinical Lab

Clinical laboratories analyze sample after sample of biological data, with the heavy responsibility of ensuring that patient test results are reliable and will not cause harm to the patient. Whether this means a misdiagnosis or a missed diagnosis, errors in clinical lab testing can have serious consequences.

“When dealing with live biologic, there is an expected degree of variation in the results,” says Serge Jonnaert, representative of Bio-Rad Laboratories, Irvine, Calif.

Historically, regulatory agencies, such as the Centers for Medicare and Medicaid Services (CMS) in the United States, have published guidelines through the Clinical Laboratory Improvement Amendments (CLIA) to determine what kind of quality control (QC) is needed to attain quality in the laboratory. While simple tests—those with a small chance of error—are waived from most CLIA requirements, moderate- and high-complexity tests are subject to guidelines that include minimum personnel qualifications and laboratory proficiency tests, as well as methods for monitoring testing equipment, ensuring proper test performance and accurate results, and generally maintaining a level of quality for all aspects of the laboratory’s ongoing operation. These regulatory requirements impose standards of quality control intended to maximize reliability of test results and ensure patient safety.

QC Products for a Variety of Needs

A variety of products can help labs assimilate information and assist in regulatory compliance. Experts assert that efficient QC programs can effectively cut laboratory data-management costs.

Unity Real Time®, by Bio-Rad Laboratories, is a data-management solution that provides statistical analysis reports to alert laboratories of their standing from a method and peer-group comparison point of view. With more than 15,000 laboratories now participating worldwide, this is the largest peer group in the industry.

“Because you’re dealing with statistics, peer group size is a big advantage,” Jonnaert says.

Unity Real Time also boasts patented functionality that varies depending on the region. With Westgard auto-rule selection and a variety of regulatory compliance integrations, Unity Real Time is considered to be a global product that can fit the needs of a customer in any country. It also offers flexible connectivity solutions, both bench and supervisory functions, and a slew of supporting educational and informative materials available via the QCNet portal.

“We have a lot of processes that customers have asked for, and we make a major investment in making sure that we have as comprehensive of a product as possible,” Jonnaert says.

This focus on research and development to answer fundamental questions on quality control has led to Bio-Rad Laboratories’ ownership and application for several QC-specific patents. One of these fundamental questions involves the frequency of QC, which parallels recent trends in QC regulations.

Another program, LabLink xL, by Thermo Fisher Scientific, is an entirely Web-based application that tracks both day-to-day QC performance and provides monthly comparison to peer groups. This purely real-time program allows users to review their data versus the peer group and create peer-comparison reports instantly. Perhaps most notably, LabLink xL boasts a balance between user simplicity and powerful, timely data assimilation.

“We pride ourselves that any person that has a basic understanding of Web browsing can use LabLink xL,” says Simon Hudd, a representative of Thermo Fisher Scientific.

LabLink xL is a huge leap forward in comparison to the previous application, LabLink Live. LabLink Live was partially real time, with data updated every 24 to 48 hours. LabLink xL, introduced in 2005, offered the first fully real-time database in the market for QC processing. LabLink xL also contains LabLink Extra, a module that provides QC supporting materials including package inserts and MSDS documents.

The second generation of LabLink xL will be rolled out in July 2009. This will include a number of enhancements to database speed, additional customizable report options, and multilanguage options, in addition to a redesign of LabLink xL communicator, which provides the quickest and most descriptive data export options and upload processes.

“Later in 2009, we are looking to introduce a number of training modules to further enhance the QC support and knowledge base that is offered with the LabLink system,” Hudd says.

User simplicity and training modules are likely to go hand in hand with recent trends in QC regulations that aim to place greater responsibility of QC determination on individual laboratories.

A third QC program, EP Evaluator 8 by David Rhoads Associates, is a method evaluation software package that offers network support, built-in backup, data transfer to and from spreadsheets, and ready-to-sign professional reports.

EP Evaluator 8, which has been on the market for less than 2 years, is the eighth version of this software and represents the result of constant improvement of David Rhoads Associates’ products. This package implements compliance with several protocols and regulatory requirements for validating and evaluating clinical laboratory methods. A free demonstration is available on its Web site, and an online version of the software package is also available with a pay-per-report system.

Regulatory Affairs

In 2003, CMS published the CLIA regulation that mandated two levels of QC each day of testing. This was thought to be an excessive requirement by many manufacturers, who believed that QC might only be necessary with every reagent lot or shipment for certain devices. Therefore, in 2004, CMS published a new set of three options known as equivalent quality control (EQC), which could reduce QC testing to once per week or once per month if laboratories were able to pass one of three screening protocols. This, too, was thought to be insufficient by many in the laboratory industry.

“A notable number of industry opinion leaders rejected EQC as being unsound. They thought it would represent a condition that would create higher risks for laboratories,” says Greg Cooper, manager of clinical standards and practices at Bio-Rad Laboratories Inc and an adviser and member of several committees/subcommittees working on lab practice standards. “The manufacturers didn’t like it, either, because they thought CMS was asking their customers to verify conditions that were already verified by manufacturers,” Cooper says.

“CMS’ translation of ‘equivalent quality testing’ in the CLIA regulations to mean ‘equivalent quality control’ in the State Operations Manual has led to reduced QC in laboratories,” says James Westgard, PhD, FACB, at University of Wisconsin Medical School.

In response to these concerns, EQC Option 4 was proposed as a Clinical and Laboratory Standards Institute (CLSI) guidance to allow manufacturers and regulators to verify claims for frequency of QC testing. Over the past 4 years, members of the CLSI EP-22 subcommittee (Presentation of Manufacturer’s Risk Mitigation Information for Users of in vitro Diagnostic Devices) have found impediments to doing what was originally intended with this document. Manufacturers would be required to share potentially cumbersome amounts of information with laboratories, and government regulatory agencies questioned statutory mandates for certifying claims about QC frequency.

A new CLSI Guidance was then born. CLSI is currently in the process of finalizing EP23 (Laboratory Quality Control Based on Risk Management), which provide QC guidelines based on risk management. This document is intended to define the type of information that lab directors need to know and consider to make good judgments about the frequency of QC in their labs. EP23 also provides direction for labs on how to use the information provided by manufacturers and aids lab personnel in identifying and mitigating potential risks in their own environment that may cause errors in results.

“EP22 and EP23 are intended to provide guidance for the laboratory director on how to develop a ‘QC plan’ on the basis of risk-management information provided by the manufacturer,” Westgard says.

Risk assessment in the lab is not truly a new concept; it is intuitive for labs to do this internally. The responsibility, however, has never been formal. Under CLIA, the lab director has always been ultimately responsible for a lab and all its operations; these new sets of documents move the obligation for determining the frequency of QC from the manufacturer to the lab director.

“This is going to be a long process, requiring lots of training, but it will eventually help labs do the right QC,” Cooper says.

International Standards

International standards differ in their level and focus of quality control measures. For example, a widely adopted international standard, published by the International Organization for Standardization (ISO) and known as ISO 15189 (Medical Laboratories—Particular Requirements for Quality and Competence), includes a guideline for laboratories to “determine the uncertainty of results, where relevant and possible.”

ISO 15189, the world’s only international lab practice standard, has been adopted worldwide, although less so in the United States. ISO-specific quality guidelines, such as uncertainty of measurement and traceability of calibration, are not yet hot topics in United States laboratories, although such ideas are likely to push their way to the forefront of discussion as manufacturers in the United States deal with more laboratories outside the United States that comply with ISO regulations. Furthermore, what these different sets of standards mean, in terms of lab quality worldwide, is that laboratories in different countries or states may be comparing apples to oranges when it comes to test results produced under different quality systems.

“Globally, the trends in quality management are driven by ISO 15189,” Westgard says.

Overall, ISO 15189 is a different set of requirements compared to those of CLIA. While many of the same people involved in CLIA—government officials, laboratory officials, and manufacturers—also worked on 15189 when it was originally written, the two sets of documents comprise different approaches. “I could see a flavor of 15189 in some areas of the CLIA regulation, but CLIA is definitely not a 15189 approach,” Cooper says.

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“I would caution people to look carefully at the new risk-management approaches to QC because they are not as quantitative as they first appear,” Westgard says. “I would also advise people not to abandon our current ‘error framework’ for managing quality. … We already have a practical measure of test quality in the form of ‘total error’ … and an established scientific literature on quality goals to guide our quality management efforts,” Westgard says.

As responsibility for QC increasingly falls on lab directors, it becomes progressively more important for them to follow and comprehensively understand QC trends and regulations.


Sara Ball is a medical writer with a background in neuroscience and science communication.