Medical Device Link.

Technology is a driving force of economic growth, especially in recent years. Advanced technologies such as microelectronics, biotechnology, and nanotechnology require measurements of higher spatial resolution, sensitivity, and selectivity. In addition, the deregulation of many mature industries, such as natural gas and electricity, calls for more-frequent and more-accurate measurements to help ensure equity in trade.

Any central government's role in metrology becomes more important as the strength of domestic industries becomes increasingly dependent on global trade. In the United States, the federal government has the constitutional responsibility to provide the weights and measures for the nation. This responsibility is vested in the National Institute of Standards and Technology (NIST; Gaithersburg, MD). NIST maintains both basic and derived SI units (units traceable to the Système Internationale) and also provides standards and calibrations that are traceable to itself (see Figure 1). NIST spends some $500 million per year (0.7% of federal R&D funds) on metrology programs and supports a $10-billion private-sector investment in measurements and standards. More than half of the $7.6 trillion in annual U.S. product sales is undergirded by this measurement infrastructure.

Figure 1. NIST measurement and standards infrastructure.

The measurement and standards framework developed by NIST is designed to address the needs of rapidly growing high-technology industries as well as mature industries. NIST provides measurements and standards for the high-tech sectors not only as tools to better characterize products, but also as tools to improve processes, enhance process yields, and maximize competitiveness in the global market. This article presents an overview of international agreements intended to support global trade and describes the role NIST plays in facilitating mutual recognition of measurements and standards.

Traceability and Comparability. A metrology infrastructure to enable global recognition of measurements and standards must exhibit two major features: vertical traceability, in order to ensure the quality and accuracy of measurements, and comparability with the standards realized and maintained by the national metrology institutes (NMIs) of various countries. Accreditation of measurement capabilities and conformity assessment for certification of products both require demonstration of measurement traceability to national standards and comparability among the national standards of the trading partners (see Figure 2).

Figure 2. National metrology institutes (NMIs) are responsible for national traceability and internal comparability. The function of comparability is becoming more critical in global trade.

The International Vocabulary of Basic and General Terms in Metrology (VIM) defines traceability as "the property of the result of a measurement or the value of a standard whereby it can be related to stated reference, usually national or international standards, through an unbroken chain of comparisons all having stated uncertainties."¹ Indeed, traceability carries an additional requirement in that it can only exist when scientifically rigorous evidence, collected continually, shows that the measurement is producing documented results for which the total measurement uncertainty is quantified. A national traceability system links field measurements to the SI by providing tools such as reference materials, reference data, and calibrations.

NMIs play a pivotal role in ensuring the comparability of physical and chemical measurements. The institutes are obligated to advance the state of measurement science in their countries in order to support the needs of domestic industry. NIST, the NMI of the United States, was founded in 1901 (as the National Bureau of Standards) and was the federal government's first physical science research laboratory. NIST provides traceability to the SI and derived units, ensuring that products and goods sold meet the claimed specifications.

Besides providing vertical traceability, an NMI also serves to link the national infrastructure to the international measurement system. NMIs have been carrying out and collaborating in international comparisons of their national measurement standards for more than a century. However, the ad hoc recognitions resulting from these historical interactions among the NMIs are no longer considered sufficient to promote international trade and ensure equity in trade. The NMI function of establishing comparability has become more critical in today's global market, and must be established on a more formal and systematic basis. The International Committee of Weights and Measures (CIPM) was a key player in the negotiation and implementation of a mutual recognition arrangement (MRA) that has been devised as a mechanism to demonstrate comparability of measurements and standards among NMIs. Details of this new MRA are discussed below.

All NMIs strive to have their measurement and standards capabilities recognized by their counterparts around the world. These efforts can facilitate the harmonization of systems of measurement and standards and eventually lead to mutual recognition among trading partners. Today's more formalized system reflects a major change in philosophy: measurements and data from each NMI are now openly shared and accessible to all. In formal comparisons, degrees or levels of comparability may be demonstrated among participants. Compatibility is defined in terms of a "degree of equivalence" that is needed for "agreement for the purpose at hand," to be decided by the end-user. This formal international measurement infrastructure spearheaded by the metrological community is in harmony with a mutual recognition agreement between the European Union (EU) and the United States that is designed to facilitate international trade.

EU-U.S. Mutual Recognition Agreement. This international trade agreement, negotiated at the highest level of government in recognition of European and U.S. economic interdependence and signed in October 1998, provides for mutual recognition of specified conformity assessment activities undertaken in the exporting country to meet the regulatory requirements of the importing country. It covers testing activities, product certification, and, where relevant, quality system registration.² Because NMIs provide the traceability to the SI necessary for these services, mutual recognition of the capabilities of trading countries' NMIs is a prerequisite for the mutual recognition of metrology services in general. The EU-U.S. agreement is designed to address regulatory issues in the areas of avionics, environmental protection, pharmaceuticals and medical devices, electromagnetic compatibility and interference, and occupational health and safety. The treaty should eliminate duplicative product testing on an estimated $60 billion worth of traded goods.³

European IVD Directive. The European Community proclaimed the necessity for legislative directives that would create a single European market as far back as the 1980s. In fact, it was the European medical products industry that identified the need for a set of directives to regulate its products. The industry sought the assistance of the European Commission in developing directives with the goal of setting specific rules to regulate the distribution of medical devices and diagnostic products throughout the European market. The intention was that a single approval would be sufficient for each product.⁴

It is not surprising that the EU-U.S. Mutual Recognition Agreement of 1998 named pharmaceuticals and medical devices as an area of focus. While that agreement engaged the NMIs, the EU's IVD Directive that was issued around the same time was the impetus for industry to take notice. The IVD Directive was published in December 1998. It requires that all IVD devices sold in Europe after December 2003 bear the CE mark. CE marking of IVD devices applies to reagents and reagent products, calibrator materials, and instruments including specimen receptacles intended by the manufacturer for the in vitro examination of human tissue, blood, or fluid samples for the purpose of providing information about a patient's state of health. The CE mark would indicate traceability of the product's measurement systems to "standards of a higher order."⁵ The implementation timetable provided options. CE marking of IVD devices could begin as early as June 2000. However, devices placed on the market prior to December 7, 2003, could be put into service until December 7, 2005.

Health-status markers that are affected by the IVD Directive are classified into two categories: Annex II, List A includes approximately 100 well-defined chemical species potentially traceable to SI units, while Annex II, List B consists of more than 500 less-well-defined chemical species potentially not traceable to SI units. Since it is generally agreed that the phrase "standards of a higher order" refers to nationally and internationally recognized certified reference materials (CRMs), it is clear that international collaboration and cooperation is necessary to meet the industry need for new standards.

Standard Reference Materials Program. NIST's CRMs sold under the registered trade name Standard Reference Material (SRM) are widely recognized and used worldwide. Approximately 1300 SRMs are currently available for use in industrial materials production and analysis, environmental analysis, healthcare measurements, and basic measurements in science and metrology. SRMs are crucial reference points in the establishment of a comprehensive measurement system for the entire nation. They are used in the United States and abroad to provide traceability, that is, an unbroken chain that connects field measurements to SI units. The process of traceability is ongoing, not stagnant.

NIST works closely with the American Association for Clinical Chemistry, Centers for Disease Control and Prevention (CDC), College of American Pathologists, National Committee for Clinical Laboratory Standards, FDA, and other organizations interested in healthcare-related standards to prioritize its standards activities and the development of SRMs. Health-related standards of particular interest to the IVD manufacturing community are the focus of the following section.

Chemical metrology is at the heart of accurate medical diagnosis and central to the development of measures to improve human health and ensure long life. Of some $1.5 trillion spent each year on healthcare in the United States, about 13% pays for measurements. More than one-third of those measurements, it is estimated, are performed for nondiagnostic purposes, such as QA/QC measurements and retests, at a cost of $50 billion to $60 billion annually. Improvements in the reliability of chemical measurements in this area clearly would have a significant economic effect. Indeed, upgrading the accuracy of just one analyte—cholesterol—has resulted in estimated cost savings of $100 million a year.

For more than 20 years NIST has developed, maintained, and refined "definitive methods" for 12 health-status markers to support the national reference system for clinical measurements (see Table I). Definitive methods are robust analytical methods for which all sources of uncertainty are known and quantified. Such methods have been instrumental in improving the accuracy and reliability of clinical laboratory measurements. For example, it has been estimated that the measurement uncertainty for cholesterol was reduced from ±18% relative in 1969 to between ±5.5 and ±7.5% relative in 1994.⁶ That improvement in accuracy has been attributed to the release of a pure cholesterol SRM in 1969 and serum cholesterol SRMs in 1981 and 1988.

NIST definitive methods are used not only for the certification of SRMs, but also to value-assign high-priority serum pools that serve as the anchor point for CDC-developed reference methods. These standards are also used by the College of American Pathologists for proficiency testing of more than 20,000 U.S. clinical laboratories. Improved accuracy of measurements, facilitated by this program, has led to better diagnosis and treatment and reduced healthcare costs. Maintaining these anchor points for the clinical measurements reference system also promotes the development and use of new technologies that are better, faster, and less expensive.

An emerging generation of health-status markers shows great clinical diagnostic promise but offers difficult new challenges for standardization. Many of the new markers are proteins, peptides, or other large biomolecules, usually present at very low concentrations. Because of the large market for tests for these new markers, many different approaches have been developed commercially. The result has been vast disagreement among results obtained with different manufacturers' test kits. NIST has focused on basic research to establish reference systems for about a dozen of these new biomarkers (see Table II).

NIST views its SRMs as the cornerstone of traceability. The institute works to ensure recognition of its standards worldwide and also to promote fair trade practices. One mechanism by which NIST ensures mutual recognition of its traceability structure worldwide is its active participation in the CIPM MRA. This MRA provides the means for implementing the EU-U.S. Mutual Recognition Agreement.

The CIPM MRA was signed in October 1999 by the directors of the NMIs of 38 member states of the Metre Convention and representatives of two international organizations. Since then, additional signoratories have joined. (The Convention of the Metre is a diplomatic treaty now agreed to by 49 nations.) The MRA provides the framework for "mutual recognition of national measurement standards and of calibration and measurement certificates issued by national metrology institutes."⁷

The CIPM MRA has the objectives of establishing the degree of equivalence of measurement standards maintained by NMIs and providing for the mutual recognition of calibration and measurement certificates issued by NMIs. A third objective derived from these is to provide governments and other interested parties with a secure technical foundation for wider agreements related to international trade, commerce, and regulatory affairs.

Implementation of the MRA involves international key and supplementary comparisons and quality systems and demonstration of competence by NMIs. CIPM consultative committees are responsible for identifying key comparisons that are needed to demonstrate comparability for a broad range of measurements. Consultative committees are organized to focus on the metrology areas of amount of substance, or mole (CCQM); electricity and magnetism; ionizing radiation; length; mass and related quantities; photometry and radiometry; thermometry; and acoustics, ultrasound, and vibration. Results of their comparisons and demonstrations are maintained in a database on the World Wide Web.

The BIPM Key Comparisons Database was originally developed by NIST for the International Bureau of Weights and Measures (BIPM), the organization under the supervision of the CIPM that ensures the worldwide uniformity of measurements and their traceability to the SI. It is now operated by the BIPM. This database (http://kcdb.bipm.fr/BIPM-KCDB/) is defined in the text of the CIPM MRA as containing appendices A, B, C, and D of the MRA. The contents of the appendices are as follows.

The principal elements of the CIPM MRA are contained in appendices B and C.

Appendix B lists the metrology areas, protocol specifications, participating laboratories, participating countries, measuring conditions, results, and associated uncertainties for key and supplementary comparisons. CIPM key comparisons are carried out by its consultative committees or by the BIPM. They are performed at the highest metrological level. Participation in the CIPM key comparisons is open to all signatories of the MRA. Key comparisons are also carried out by regional metrology organizations (RMOs) such as the Systema Interamericano de Metrologia, European Collaboration on Measurement Standards, and Asia-Pacific Metrology Programme. The RMO key comparisons must be linked to corresponding CIPM key comparisons by means of joint participants (see Figure 3). RMOs may also carry out supplementary comparisons that address regional needs not covered by key comparisons, in order to provide confidence in calibration and measurement certificates.

Figure 3. The interconnectivity among the regional metrology organizations (RMOs), the International Bureau of Weights and Measures (BIPM), and the International Committee of Weights and Measures (CIPM) consultative committee. The RMOs serve to link their respective regions to the international measurement infrastructure.

The CIPM CCQM is the committee responsible for the realization of the SI unit "mole" and for demonstrating the comparability of all chemical composition–related measurements. The CCQM key comparisons currently are focused on measurements related to healthcare, food and nutrition (including drinking water), the environment, advanced materials, commodities, forensics, and general analytical applications (e.g., calibration solutions, high-purity materials, acidity, and conductivity).

NIST is the pilot laboratory for several of the CIPM key comparisons, including CCQM-K6, cholesterol in human serum. This comparison has been completed, and its report is in a final draft stage. Planned key comparisons that address clinical needs are glucose in serum and creatinine in serum. One that has been completed is CCQM-K2, lead and cadmium in water. The data have been reviewed and approved for posting in the database; therefore, they can be discussed here as an example (see Figures 4 and 5). A matrix of equivalence in the BIPM Key Comparisons database displays, along with the analytical results, a statement of the degree of equivalence between each pair of laboratories. This is defined in terms of the magnitude of deviation (Di) and uncertainty in the deviation (Ui) from the key comparison reference value. The matrix is accompanied by a graphic representation of the same data, as shown in Figure 5. A controlling authority can use the results in the BIPM Key Comparisons Database to determine whether the degree of equivalence demonstrated between two NMIs (the Dij and Uij cells in the matrix) is sufficient for the purpose at hand, such as regulatory compliance or international trade.