Creating a common language for labs
You’d think that laboratorians from New Jersey to New Guinea
would speak the same language by now, at least when it comes to
professional terms, but you’d be wrong.
The United States, European nations, and other countries, such as Japan, define the
same basic words very differently in some cases, and the division
is creating problems for vendors, regulatory and standards-setting
agencies, journal editors, patients, and clinicians.
Although this is a longstanding problem, our increasingly global society has made
it worse. Not only are vendors selling the same products in many
countries, but patients travel internationally and expect to get
the same diagnostic test results in Frankfurt as in Honolulu. Clinicians
are practicing across borders; laboratories are becoming regional,
national, and even international in scope.
It all adds up to a need to harmonize terms, such as sensitivity, specificity,
accuracy, trueness, analyte, specimen, and error, so the meaning
is consistent throughout the world.
“It’s a big problem growing bigger because the marketplace [for diagnostic
testing] has evolved into a global marketplace,” says Steven Gutman,
MD, director of the FDA’s Office of In Vitro Diagnostic Device
Evaluation and Safety.
Dr. Gutman, a champion of harmonization, says the United States and Europe,
in particular, took different paths in their approach to the use
of common diagnostic terms. “One of the major differences
is that our regulatory model is equivalency based, while the European
model is standards based,” Dr. Gutman says.
That means the United States tends to be more reactive to established practice
in setting regulatory terms, while European regulatory bodies and
international/European standards groups such as ISO and CEN “are
very much oriented toward precise definitions of analytical performance,” he explains.
For example, “accuracy” in the United States generally means agreement
between the mean or best estimate of a quantity and its true value,
and it is a measure of systematic but not random analytic error.
In Europe, “accuracy” is a measure of both systematic
and random analytic error, while “trueness” is a measure
of systematic error and corresponds to the U.S. definition of accuracy.
The difference between analytical and diagnostic sensitivity and specificity “is
a problem on both sides of the ocean,” Dr. Gutman says. “It’s
a matter of trying to clarify which one you mean.” The term
“analytical sensitivity,” for example, is considered
by some to represent the smallest amount of a substance that can
be measured in a sample and by others to represent the slope of
the calibration function, while “diagnostic sensitivity”
refers to the percentage of people with a disease who test positive
for it with a given test.
Although the terminology gap is particularly taxing to vendors, because they
must prepare separate package labels for the same product when it
is sold in different countries, it can also create headaches for
organizations such as the CAP, which accredits labs worldwide and
provides them with proficiency tests, says Gerald Hoeltge, MD, head
of transfusion medicine at the Cleveland Clinic Foundation and CAP
representative to the NCCLS.
“It’s expensive for vendors. They’d like to make one set of instructions
as a package insert in every country,” Dr. Hoeltge says. “It’s
also a significant issue for the lab accreditation and Surveys programs
for CAP because they deal with labs all over the world.”
If a CAP resource committee writes up participants’ results from a Survey in
U.S. terms, participants in other countries could be confused, he
explains. The checklist questions for the CAPLaboratory Accreditation
Program are in English, bypassing the translation barrier, but the
terms are U.S.-based. “If the wrong words are being used for
someone in another country, it complicates and confuses,” Dr. Hoeltge says.
Take a laboratory in Germany that’s CAP-accredited but performs testing in an
area where the CAP doesn’t have a proficiency test. “They
will be submitting their data based upon a European proficiency
testing or audit program,” he notes. “That puts the
CAP in the position of interpreting another country’s survey
summary. If everybody were using the same terms in the same way,
life would be much simpler.”
Vendor groups and standards bodies on both sides of the Atlantic are trying to
improve the situation by rewriting package labeling and standards,
but the process will probably take a generation to complete because
textbooks and training must also be revised.
NCCLS leads the way
Leading the effort is the NCCLS, which oversees laboratory standards
in the United States and serves as administrator of ISO/TC 212,
an international technical committee working on standardization
in laboratory medicine. “If you’re going to have cost-effective
services and products, you need globally applicable standards to
minimize confusion,” says John V. Bergen, PhD, executive director
of the NCCLS. When it comes to nomenclature, “the big outlier
is the U.S.,” he adds.
Three harmonization programs are underway at the NCCLS.
First is the Harmonized Terminology Database, developed by the executive staff
to give direction about nomenclature for the clinical laboratory
and in vitro diagnostics to the volunteers who write NCCLS standards
and to the editors and writers of professional journals. “It
will let people know the most internationally accepted definitions
of common terms,” Dr. Bergen says. “The goal is to see
if, over time, the editors of professional journals could put statements
in their instructions to authors encouraging them to use the database.”
The second is ensuring that, as new standards are developed and existing ones
revised, the language in them is harmonized. This NCCLS revision
process is handled through the Chairholders Council, the volunteer
body that oversees standards projects, with the assistance of a
special harmonization team drawn from industry, regulatory bodies,
professional societies, and other interested groups.
“You can’t do this overnight,” Dr. Bergen cautions. The NCCLS oversees
150 published standards, each of which is supposed to be reviewed
every three to seven years. “Within five years we should be
through most of the documents,” he says.
Any time the NCCLS considers a new standard, “we talk to the team about
the need for harmonization and encourage them to identify a member
who will be the harmonization champion and look over the document
to identify terminology issues,” Dr. Bergen says.
NCCLS president Donna Meyer, PhD, director of community health for Christus Health
System, headquartered in Dallas, says that where appropriate in
new documents, “we will put in synonyms for terms” so
different groups of readers will understand them. She singles out
the European concept of trueness as one instance where that would
be appropriate; another is the use of the term analyte (measurand
in Europe). “These will not be geared just to a U.S. audience,”
she says. The synonyms probably will be used for a few years to ease the transition
to harmonized terms.
The third harmonization program involves outreach to editors and writers of medical journals,
textbooks, and other materials through a task force formed by the
NCCLS board’s Global Programs Committee and Membership and
Marketing Committee. “We’re developing a communication
plan for talking with professional organizations and journal editors
to get this [standards harmonization] into textbooks and other constituencies
where tomorrow’s physicians learn,” Dr. Meyer says.
“Textbook and journal editors and writers are vital to the process,”
she says. “It doesn’t do any good to put out standards
documents that people don’t understand or use.” Dr.
Meyer also wants to make sure the outreach includes academic communities
and practicing labs.
In all of these efforts, the NCCLS will adopt ISO-accepted meanings for terms such
as sensitivity, specificity, and accuracy, Dr. Bergen says. That’s
because ISO is an international organization composed of member
countries spanning the globe.
“That doesn’t mean there won’t still be national standards”
for specific uses, he adds. For example, laboratory waste practices
in the United States are “linked toU.S. regulatory requirements
and require U.S.-focused guidelines to help labs,” Dr. Bergen
Dr. Meyer notes that the effort to harmonize will have to filter through “the
communities we serve” before it becomes effective. Despite
a big push to introduce the metric system in the United States,
“How far have we gotten?” she asks, to illustrate the
difficulties groups like the NCCLS face in attempting harmonization.
Vendors chime in
Vendors on both sides of the Atlantic, however, are pushing for
harmonization. In the United States, Kay Setzer, manager of external
standards for Abbott Laboratories, is chairing a working group—part
of ISO/TC 212—that is developing global standards for labeling
in vitro diagnostic products.
“Labeling has become a big problem because countries tend to put their own
meanings in their regulations,” Setzer says. “If you
make a product you want to sell globally, you have all these separate
requirements to satisfy.” Even the designation for the product
information differs—the United States calls it “labeling,” while Europe calls it “information
supplied by the manufacturer.”
More than 45 countries have some regulations on in vitro diagnostic products,
and “every year more are added to the list,” Setzer
says. “Every year there’s more confusion on what needs
to be put on the labeling.”
Setzer’s working group is trying to harmonize “exactly what is required
on a label, a package insert, or the actual container—both
the terms themselves and the parameters of what needs to be included,”
she says. Industry representatives and laboratory professionals
from the United States, Japan, Canada, Korea, and Europe participate.
As Setzer’s group finishes its standards—four are underway now—it
circulates them for review within ISO/TC 212. The committee’s
approximately 35 member countries “will have comments and
additions,” she says. “Then ISO will vote on the final
document to be accepted as an ISO standard.”
Setzer’s group is also working with the Global Harmonization Task Force (www.ghtf.org), which is composed of regulators (including Dr. Gutman) from the
United States, Japan, Canada, Europe, and Australia. “They’re
trying to set down a group of requirements for medical devices,”
she says, including the best way to regulate labeling.
The hope is that the regulatory bodies within the countries will adopt the ISO
standards developed by her working group. “We want everybody
to follow those standards,” Setzer says. “If the regulatory
bodies adopt them, that would be a great step forward.”
Like others involved in harmonization, Setzer warns that there are no quick
fixes. She hopes ISO will adopt her working group standards by early
2005, if not before. “Then they will be available to regulatory
bodies like the FDA,” she says. “It’s a long-term
In Europe, Emil Voelkert, PhD, senior vice president of Roche Diagnostics, Mannheim,
Germany, chairs the European Diagnostic Manufacturers Association
(EDMA) working party on standardization. “Harmonization of
terms is one aspect of our work,” he says. “In standards
development, we see a definite trend away from national to regional and international
ISO 15189, for example, provides a global basis for accrediting labs. “Standards
in the ISO world are horizontal, meaning they provide a general
framework without going too much into specifics,” he says.
Dr. Voelkert agrees with Setzer that industry needs a common basis for marketing
identical products. “Quality should have the same facets anywhere,”
he adds. “And for the users and patients, the harmonization
of concepts is providing the basis for better compatibility of results
The EDMA working party monitors and provides input to a number of standardization
projects, including those in ISO/TC 212; ISO/TC 210, which deals
with general medical devices; and CEN/TC 140, which deals with in
vitro diagnostic medical devices.
The EDMA also is monitoring efforts by such groups as the Global Harmonization
Task Force and Setzer’s group and is providing input from
industry with the European perspective.
Another important international endeavor, says Dr. Voelkert, is the Joint Committee
on Traceability in Laboratory Medicine (JCTLM), which aims to establish
internationally comparable reference systems. This represents “another
facet of harmonization and will provide the basis for comparable
results over region and time,” he says. For example, “the
results for glucose or cholesterol in the United States would be
the same as in Europe, Canada, Australia, Japan, and all other countries.”
Dr. Voelkert believes all these efforts, including those of the
NCCLS, “are on the right track.” As far as harmonization
of terms is concerned, there are, in reality, only 15 to 20 critical
terms “where we need to get acceptance, particularly in the
English-speaking world.” Of course, “once you devise
a solution, you have to implement it,” he says, but he believes
that will happen, albeit slowly. “I am optimistic,”
Acceptance will be gradual
Part of the process of accepting new standards or harmonizing terms
will fall to medical journals. Kenneth McClatchey, MD, DDS, editor
of the Archives of Pathology & Laboratory Medicine,
says he’s prepared to support the NCCLS’ efforts, including
using the new database.
Harmonization was a problem “even before I was a pathologist,” says
Dr. McClatchey, professor of pathology at Loyola University Medical
Center, Chicago. “NCCLS is the driving force because it administers
ISO/TC 212,” he says. ISO’s new international standard
on clinical lab management, 15189, should propel labs toward harmonization,
Dr. McClatchey plans to refer authors to the NCCLS database “to make sure
the terminology they’re using is in sync with international
standards.” Even with articles in the United States, he says,
“we’re consistently dealing with terminology that one
person uses one way and another person a different way.”
The CAP, which has a close relationship with the NCCLS, should take a leadership
role in the harmonization effort, asserts Dr. McClatchey. “We
in the U.S. will have to deal with international standardization.
The globe is shrinking,” he says. “The lab business
is an international business as much as manufacturing [of diagnostics]
is an international business. We need an international understanding
of terms and methodologies.”
Professional organizations, as well as government and industry groups, need to
back the NCCLS, he adds. The CAP has an inherent interest because
harmonization “will benefit our external quality assessment
David Bruns, MD, editor of Clinical Chemistry and professor of pathology at the
University of Virginia, Charlottesville, agrees that standardizing
terms is important in journal literature.
For instance, the term sensitivity (meaning analytical sensitivity) can be confusing
because “a lot of people think it means the detection limit
when really it is the slope of the calibration curve,” he
says. “This is an example of where we have a Tower of Babel.”
Consequently, Dr. Bruns has banished the word sensitivity from his journal. Instead,
he asks writers to use “detection limit,” which is “almost
always what they mean—how much of the substance you need to
get a measurable signal.”
Dr. Bruns approaches “analytical specificity” the same way. “The author
needs to spell out exactly what was done,” he says. “If
you have an assay for insulin, if it’s specific, it’s
not going to react with other similar
hormones.” Here again, he prefers that authors use more precise
terms, like “cross-reactivity.”
As for the NCCLS database, Dr. Bruns believes it could be useful, “but we’d
have to see how it comes out.” He hopes the NCCLS will open
the database to comment before deciding on a final version. “You
have to involve editors in the process if you want them to use it,”
The database is a “living” work in progress, responds the NCCLS’
Dr. Bergen, and comments intended to improve the interface’s
utility and user friendliness will always be welcome. “We
can also review and process input on specific terms and definitions,”
he says. But because the purpose of the database is to promote the
use of internationally standardized terminology, says Dr. Bergen,
“such [outside] input would need to be referred to and formally
considered within the international standards system.”
In Dr. Hoeltge’s view, it will be a generation before everyone
is on the same page in laboratory and diagnostic lexicon. That’s
because the transition won’t occur entirely until “pathology
residents and young clinical scientists become tomorrow’s
leaders.” For now, Dr. Hoeltge communicates with his clinicians
at the Cleveland Clinic in ways they understand. “If you didn’t
use a term in training,” he says, “it’s hard to
Karen Southwick is a writer in San Francisco.