Medical Device Link.

Originally Published IVD Technology July/August 2001

Toward a standards-based future: ISO/TC212 standards update

Donald M. Powers

Donald M. Powers, PhD, is president of Powers Consulting Services (Rochester, NY), an independent IVD regulatory and quality consulting firm, and convener of ISO/TC212/WG3. He can be reached via e-mail at powers@frontiernet.net.

At its annual meeting, held last month in Dublin, Ireland, the International Organization for Standardization (ISO) technical committee on clinical laboratory testing and IVD test systems, ISO/TC212, continued to advance 15 important IVD standards and technical reports.

Eight of the standards will be harmonized with the Brussels-based European Committee for Standardization (CEN) standards in support of the European Union's IVD Directive. Seven documents approved by ISO member countries as draft international standards (DIS) will be circulated for a final DIS vote after one last revision to address voting comments. Once approved, these standards may begin to influence how the IVD industry is regulated.

This article looks at the major issues facing each of the working groups, and mentions some of the issues related to the ISO/TC212 standardization process. More countries seem to be leaning to the European standards-based regulatory model than to the more prescriptive U.S. regulatory model, so having a nucleus of international IVD standards in place might help tip the balance in favor of standards-based regulations. FDA is also moving toward recognizing international standards, albeit cautiously, in the interest of global harmonization.

Calibration Traceability. This series of standards includes ISO 17511, ISO 15193, ISO 15194, ISO 15195, and ISO 18153. Mandated by the IVD Directive, the series is intended to ensure that calibrators used in IVD systems are accurate. The directive requires that calibrators must be traceable to a higher-order reference material or reference method, if one exists.¹ This requirement, the traceability and reference system standards, and the activities they have spawned at the National Institute of Standards and Technology (NIST) and other metrology institutes, have been discussed in detail in recent articles in IVD Technology. ^2–6

The problem with the metrological concept of traceability is its focus on the accuracy of calibrator values, rather than on the accuracy of patient sample results. Accurate calibrators do not guarantee accurate patient results, and may even introduce bias into the patients' results. This phenomenon is termed a matrix effect and is caused by the influence of the sample and/or calibrator matrix on the measurement. The logic flaw in the directive cannot be corrected by a standard. However, constructive participation by a few manufacturers resulted in significant improvements in the traceability standard that will allow manufacturers some flexibility to avoid this pitfall. This is a good example of the critical importance of ensuring constructive participation by those who will be affected by a standard.

One warning to IVD manufacturers is in order: If the right steps are not taken to conform to ISO 17511, the traceability requirement could make current assays ineligible for the CE mark, and thus force them off the European market. An excellent guidance document for interpreting the calibration traceability standard is available on the Web site of the European Diagnostic Manufacturers Association (EDMA).⁷

Global Labeling. An initiative is under way to create an international standard for labeling requirements. Working Group 3 (WG3) has developed a preliminary "gap analysis" to identify conflicts and inconsistencies among existing national regulations. The project team, led by Kay Setzer of the United States, met in Dublin to examine the labeling regulations of the United States, Japan, and the European Union's IVD Directive, as well as the European labeling standards. Their initial review highlighted enough significant differences to conclude that an attempt to develop an international standard would be premature, so WG3 decided that its first priority would be to publish a report on the current state of IVD labeling regulations. The preliminary gap analysis will be shared with the Global Harmonization Task Force (GHTF) at its July meeting in Washington, DC; medical device labeling, including IVDs, is on the agenda.

Once a detailed gap analysis is completed, WG3 will explore ways to create a harmonized international standard, that is, one that can be used by the European Union to support the IVD Directive as well as by other countries around the world.

Blood Glucose Monitors for Self-testing. Since the first DIS missed approval by one vote, ISO 15197 is undergoing a second DIS vote by ISO and CEN-member countries. The negative votes were due to concerns over the minimum accuracy requirement and over the use of terminology inconsistent with the ISO vocabulary. The accuracy requirement was expected to be controversial, but the terminology issue caught the working group by surprise.

The degree of accuracy required for glucose monitoring continues to be debated, with the American Diabetes Association setting an aggressive goal of no more than 5% total error due to bias and imprecision.⁸ Manufacturers acknowledge this as a goal, but claim that state-of-the-art glucose meter technology cannot do better than ±15–20 mg/dl below glucose concentrations of 100 mg/dl. Manufacturers point to extensive clinical studies that have shown that the current generation of meters is effective in managing diabetes and argue that the role of standards is not to drive product improvements, but to establish minimum criteria for acceptable devices.

The project team, led by Peter Mueller of Germany, sought additional medical input and reached a compromise that tightens the requirement to ±15 mg/dl below 70 mg/dl. The results of the second vote are expected in the fall.

Oral Anticoagulation Monitors for Self-Testing. ISO 17593 is the second vertical product standard being developed by ISO. At the Dublin meeting, TC212 approved circulation of a committee draft—the first stage in the process of producing an ISO standard—based on a consensus of the working group.

The project team, led by Michael Spannagl, a physician from Germany, is attempting to ensure that a broad spectrum of expert medical input is obtained in setting the performance requirements. The participants in Dublin, evenly divided between diverse manufacturers and nonmanufacturers, are addressing technical challenges related to methods of standardizing measurements and evaluating the accuracy, trueness, and precision of self-testing measurements using unstable fresh blood samples. The working group expects to submit a DIS for an ISO vote in 2002.

Biological Stains. Originally developed by CEN, ISO/TC212 submitted EN 12376 to ISO members as a DIS under the terms of the Vienna Agreement between CEN and ISO.⁹ ISO/DIS 19001 passed without dissent although several suggested improvements were received as voting comments.

A project team led by Hans Lyon of Denmark evaluated the comments and recommended deferring action until the EN standard is up for revision. Otherwise, global manufacturers would have to deal with an ISO and a CEN standard on the same subject.

Performance Goals Based on Medical Needs. Manufacturers have requested a standard describing a systematic process for setting performance goals based on medical needs, which could be used to establish user requirements for IVD assays under design controls. Lawrence Kaplan of the United States was selected to lead the project.

After extensively debating the mer-its of several approaches, the working group decided that a consensus standard was premature. The main approaches were outcome studies, biological variation and physician interviews, each supported by strong advocates as the preferred approach. The working group decided to issue a technical report that would describe each approach and provide guidelines for its application. The report, ISO 15196, is being written for clinical laboratories, which can use its requirements to select IVD systems and for IVD manufacturers, which can use it to establish performance requirements for new assays. The final vote is expected by year end.

Validation of Manufacturers' Recommendations for User Quality Control. Originally proposed by U.S. manufacturers to provide a basis for an exemption from CLIA-mandated traditional quality control (QC) requirements, ISO 15198 is out for its first vote as a DIS. Led by Mario Werner, MD, of the United States, the project team developed a standard with broader application to all IVD systems. The current version incorporates industry input, but may not have sufficient concrete guidance to help a manufacturer decide whether its QC recommendations require formal validation studies and if so, how the studies should be designed. An auditor might conclude that any recommendations would require formal validation studies to demonstrate that the number of levels, the specific concentrations, and the frequency were sufficient to meet user requirements for an effective quality control procedure.

There is an attempt to grandfather existing systems relying on traditional QC, but traditional QC is not defined and each new or modified assay will have to face the question. QC recommendations based on application of the well-understood Levey-Jennings-Shewhart statistical principles should be justified, but explicitly exempted from formal validation.

Until recently the project suffered from lack of attention by manufactur-ers because they felt the standard was no longer needed. However, that realiza-tion came too late to stop its forward progress.

When an international standard comes into existence, especially one addressing a perceived important need, there is a strong possibility that it will become an expectation of customers, professional associations, and regulatory agencies. A possible scenario might be as follows. Once approved, FDA will list ISO 15198 as a recognized standard. Regulatory guidance documents and product standards will begin to reference it, and major laboratory customers, especially outside the United States, will ask to see a declaration of conformity. To lend support to this possible outcome, ISO 15198 has already been incorporated as a normative reference (i.e., an additional required standard) in the draft standard on anticoagulation monitoring devices.

The voting period for ISO 15198 ends September 5, 2001. Those interested in reviewing a copy of the standard should contact their national standards body or trade association. The U.S. technical advisory group (TAG) is developing the U.S. position on ISO 15198 and would welcome constructive input. U.S. TAG members may obtain a copy of the standard from NCCLS.

Labeling Symbols. The IVD Directive encourages manufacturers to use recognized graphical symbols when-ever possible. TC212 acts as a clearinghouse for symbols proposed for use with IVD products. Carolyn Jones of the United States is the liaison to ISO/TC210, the committee that develops standards for medical devices and maintains a compilation of ISO symbols approved for use with medical devices (ISO 15223).¹⁰

Figure 1. Symbols recommended by ISO/TC212 for use with IVD product labeling.

Companies and organizations that would like to propose a new symbol for IVD labeling should submit it to TC212 through their national ISO member organization or liaison, such as EDMA. U.S. manufacturers should submit candidate symbols to Carolyn Jones at AdvaMed, who will submit these proposals through the U.S. TAG.

Medical Laboratories—Particular Requirements for Quality and Competence. Working Group 1 developed ISO 15189 as an alternative to ISO/IEC 17025, which was developed for calibration and industrial testing laboratories.¹¹ ISO/IEC 17025 has seen increasing use for accrediting clinical laboratories in some countries, and occasionally has caused laboratories to take extraordinary measures to maintain their accreditation. Thus manufacturers and some accreditation agen-cies, such as the College of American Pathologists, have supported an alternative that recognizes the unique nature and special requirements of clinical lab testing.

Originally titled "Quality Management for Medical Laboratories," ISO 15189 has been given a new title and will be revised to avoid confusion with ISO quality management standards. It will be submitted to ISO for final DIS vote after review by ISO/TC176, which oversees ISO quality management standards, and ISO/CASCO, which oversees ISO standards used for accreditation. These committees have to be satisfied that the work done by TC212 fits into the overall ISO strategy. A companion guidance document, ISO 22869, and a similar standard for point-of-care testing, ISO 22870, are also being developed by Working Group 1.

Medical Laboratories—Requirements for Safety. ISO 15190 is a well-written standard on clinical laboratory safety. The DIS was approved without significant controversy and is being revised to address the voting comments. The revised standard will be submitted to ISO as final DIS.

Next Steps. All three working groups have announced plans to meet in the fall to continue work on their projects. Working Group 1 plans to meet to complete the revision of ISO 15189, laboratory quality and competence. Working Group 2 will meet to address comments received on the two traceability standards. Working Group 3 will meet to continue development of the labeling technical report; to address voting comments on ISO 15198, validation of QC recommendations, and ISO 15197, blood glucose monitoring systems; and to move these standards to the final stage in the ISO process. The times and venues will be announced by NCCLS three months before the meeting.

Several standards should be circulated for a vote in the fall. These include ISO/CD 17593, anticoagulation monitoring systems; and ISO/TR 15196, performance goals. Manufacturers and other stakeholders are advised to obtain copies, review them carefully, and provide comments through one of the many routes available—such as via their national standards organization (e.g., ANSI/ NCCLS, DIN, AFNOR) or through a liaison organization (e.g., IFCC, WASP, EDMA), or a member of a liaison organization (e.g., AACC, CAP, BIVDA). U.S. manufacturers can also provide comments through AdvaMed, which is a member of the U.S. TAG.

References

1."Council Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on In Vitro Diagnostic Medical Devices," Official Journal of the European Communities L331 [7 December 1998]. (Also available on the Internet at http:// www.edma-ivd.be.)

2.Donald M Powers, "Traceability of Assay Calibrators: The EU's IVD Directive Raises the Bar," IVD Technology 6, no. 4 (2000): 26–33.

3.Neil Greenberg, "Calibrator Traceability: The Industry Impact of the IVD Directive's New Requirements," IVD Technology 7, no. 2 (2001): 18–27.

4.Donald M Powers, "Calibration Traceability: NIST Workshop Takes a Major Step Forward," IVD Technology 7, no. 1 (2001): 26–30.

5.Hratch G Semerjian and Ellyn S Beary, "Mutual Recognition of Measurements: Its Potential Impact on International Trade in IVDs" IVD Technology 7, no. 4 (2001): 47–54.

6.Lothar Siekmann, "Measurement Traceability in Clinical Chemistry Analyses," IVD Technology 7, no. 1 (2001): 41–50.

7.European Diagnostic Manufacturers Association, "Interpretation of the CEN/ISO Standards prEN ISO 17511 and prEN ISO 18153 on Metrological Traceability of Values Assigned to Calibrators and Control Materials."

8.American Diabetes Association, "Self-Monitoring of Blood Glucose," Diabetes Care 1994; 17(1): 81–86.

9.In Vitro Diagnostic Medical Devices—Information Supplied by the Manufacturer with In Vitro Diagnostic Reagents for Staining in Biology, EN 12376 (Brussels: European Committee for Standardization, 1999).

10.Medical Devices—Symbols to Be Used with Medical Device Labels, Labeling, and Information to Be Supplied, ISO 15223 (Geneva: International Organization for Standardization, 2000).

11.General Requirements for the Competence of Testing and Calibration Laboratories, ISO/IEC 17025 (Geneva: International Organization for Standardization, 1999).

Copyright ©2001 IVD Technology