www.elsevier.com/locate/jelectrocard

Journal of Electrocard

Use of standards in the review of medical devices

Charles HoT, Donald Jensen, Frank Lacy, Neal Muni, Sabina Reilly, Elias MallisDepartment of Health and Human Services, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Rockville, MD 20850, USA

Received 10 June 2005; accepted 10 June 2005

Abstract In keeping with its mandate to provide the least burdensome means of product regulation, the US

0022-0736/$ – see fro

doi:10.1016/j.jelectroc

T Corresponding

Food and Drug Administration’s (FDA) Center for Devices and Radiological Health uses many

different standards to facilitate the review of premarket submissions of medical devices. The benefits

of using standards in this manner include providing a set of common requirements and test protocols

to the device manufacturer, thus reducing the manufacturer’s need to breinvent the wheelQ for eachnew bench test to ensure safety and effectiveness of the device. With the current trend toward

international harmonization of standards, tests performed in accordance with an international

standard may be acceptable to several countries. However, there are instances in which the FDA does

not agree with certain provisions in a standard. This article aims to clarify the approaches taken by

the FDA to balance or resolve issues that arise when there is disagreement regarding the acceptability

of a particular standard. One approach begins with the recognition of only some provisions of a

standard, or more commonly, excluding those parts of a standard that are unacceptable to the FDA

for regulatory or scientific validity reasons. Other approaches include working with the standards

development organizations to revise the standard to include language more agreeable to all parties

involved. Specific examples will be presented on medical devices, such as electrocardiogram cables

and connectors, and noninvasive blood pressure monitors.

2005 Published by Elsevier Inc.

Keywords: FDA; Medical devices; Standards; Pressure band method

1. Introduction

The US Food and Drug Administration’s (FDA) Center

for Devices and Radiological Health uses many recognized

standards to facilitate the review of premarket notification

(510(k)) submissions of medical devices. Section 514(c) of

the Food, Drug, and Cosmetic Act, as amended, provides

explicit authority to use FDA-recognized standards in the

premarket review of medical devices. Many benefits are

accrued by using standards in this manner, including the

ability to provide a set of common requirements and test

protocols to the device manufacturer, thus reducing the need

to breinvent the wheelQ for each new bench test to ensure

safety and effectiveness of the device. Furthermore, with the

present trend toward international harmonization of stand-

ards, tests performed in accordance with an international

standard may be acceptable to several countries, facilitating

nt matter 2005 Published by Elsevier Inc.

ard.2005.06.030

author.

simultaneous product approval applications to multiple

international regulatory bodies. In addition, the use of

standards may reduce the need for supporting documents in

the premarket notification submissions, as in the case of

Special 510(k)’s. In this article, unless otherwise stated, the

term standards refers to bvoluntary consensus standards.QBefore the agency can officially recognize a standard, the

standard is reviewed for compatibility with agency regula-

tory and scientific needs. Subsequent to this review, an

associated bsupplementary information sheet Q is developedto accompany the recognized standard. This information

sheet documents the extent of the standard’s recognition,

and whether or not any additional documentation, such as

summary report of test results, is needed. The rationale for

the supplementary information sheet is that when a

manufacturer declares conformity to the standard, the

agency can have a better understanding of the extent of

the conformity.

In most cases, a recognized standard is accepted in its

entirety by the agency. In rare occasions, however, the FDA

iology 38 (2005) 171–174

C. Ho et al. / Journal of Electrocardiology 38 (2005) 171–174172

may not completely agree with the provisions of the

standard, necessitating certain steps to resolve specific

differences. This article aims to clarify the steps taken by

the FDA to balance or resolve such differences, using

illustrative device regulatory submissions as examples for

which differences in FDA and technical standards were

identified and then resolved.

2. Conflict with a Federal regulation

One reason why the FDA might not be able to accept a

voluntary consensus standard is that some provisions of a

standard actually conflict with Federal regulation. In this

case, the FDA must follow its regulatory mandate instead of

the consensus standard.

For example, the Code of Federal Regulations (CFR) spe-

cifies a mandatory bperformance standard for electrode lead

wires and patient cablesQ (21 CFR 898). Many electrical/

electronic devices, such as electrocardiogram monitors,

pulse oximeters, and apnea monitors, include patient cables.

In 21 CFR 898, the Federal performance standard ensures that

the distal connector of a patient cable (the connector located

farthest from the patient) cannot be accidentally plugged into

the AC power outlet.

The regulation, under 21 CFR 898.14 (b), sets forth cer-

tain test requirements and test methods for verifying com-

pliance with this Federal performance standard. However,

the voluntary consensus standard, ANSI/AAMI EC12:2000,1

section 5.3.2, sets forth the verification test as inspection and

does not specify a test finger for verifying compliance.

Because this clause of the EC12 standard disagrees with the

Federal regulation, the FDA supplementary information

sheet indicates that this clause is not recognized. The

manufacturer is required to use the test methods set forth

in 21 CFR 898.14(b). The regulation also specifies that under

special circumstances, the FDAmay grant waivers to devices

used for special purposes.

Another example of a consensus standard being in

conflict with Federal regulations is the use of the English

language in a device’s Instructions for Use document.

Although the regulation under 21 CFR 801.15(c) requires

the use of the English language, except in Puerto Rico, the

NOTE in section 4.1 of EC12:2000 recommends the use of

symbols under AAMI/ISO TIR 15223, without any textual

instruction. As a result, this clause of EC12:2000 is not

recognized by the FDA. The supplementary information

sheet hence indicates that the manufacturer is required to use

the English language in the Instructions for Use. One

notable exception is the use of the symbol bRx Q to indicate

bprescription use only.Q

1 The acronyms ANSI and AAMI represent the American National

Standards Institute and Association for the Advancement of Medical

Instrumentation, respectively.

3. Differing interpretations of standard

Another reason for the FDA to not accept a consensus

standard is a difference of scientific opinion in the technical

validation used to justify the implementation of a standard

and/or its interpretation. An example is the pressure band

method used in clinical tests of noninvasive blood pressure

(NIBP) monitors.

The voluntary consensus standard, ANSI/AAMI SP10

(1992 and 2002 versions),2 has been used by many NIBP

monitor manufacturers to validate the NIBP monitor against

an invasive reference device (such as an indwelling arterial

catheter). This standard can also be interpreted to allow

the use of the pressure band method. However, the FDA

is concerned about potential deficiencies in the scien-

tific validity of the pressure band method. They are dis-

cussed below.

3.1. Pressure band method

An NIBP monitor usually requires at least 10 seconds to

record one set of systolic, diastolic, and mean pressure

readings. In contrast, an invasive reference device (eg, an

indwelling arterial catheter), continuously records several

sets of systolic, diastolic, and mean pressure readings

during this 10-second period. The method for comparing

the NIBP monitor’s single set of readings with the several

sets of reference device readings is not clearly articulated in

the standard.

In the alternative method indicated in SP10:2002, clause

C3, paragraph 2, only the single maximum and minimum

values of the systolic pressure readings of the reference

device recorded during this 10-second period could be used to

define a bpressure bandQ for systolic pressures recorded by thereference device. In similar fashion, a diastolic pressure band

can be defined using only diastolic pressure values.

Although the SP10 standard does not specify the

method of comparing the NIBP monitor and the invasive

reference device, some manufacturers have used the inter-

pretation below.

If a subject device’s systolic pressure reading lies within

the pressure band (ie, if the subject device’s reading is less

than the maximum, but greater than the minimum, recorded

by the invasive reference device), the difference between

subject device and reference device is scored as bzero.Q Ifthe subject device’s systolic pressure reading lies outside the

defined pressure band, only the distance between the subject

device reading and the edge of the pressure band is scored

as the difference between subject device and reference

device. Some manufacturers refer to this as the bpressureband method.Q An illustration of this method is provided

using artificial data.

2 ANSI/AAMI SP10:2002 is the consensus standard entitled,

bManual, electronic, or automated sphygmomanometers.Q The 1992

version is the older version of the standard and covered only automated

sphygmomanometers.

Illustration on Pressure Band Method

0

20

40

60

80

100

120

140

160

0 2 4 6 8 10 12

Time (s)

Sys

tolic

Pre

ssu

re (

mm

Hg

)

Invasive reference data NIBP monitor data

C.Hoet

al./JournalofElectro

cardiology38(2005)171–174

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C. Ho et al. / Journal of Electrocardiology 38 (2005) 171–174174

The 1987 version of the SP10 standard and some

international draft standards (DIN 58130 and prEN 1060-4),

in fact, provide numerical examples using the pressure

band method to compare blood pressure readings from

the NIBP monitor and the invasive reference device,

although the pressure band method is not stated by name

in these documents.

3.2. Issues with the pressure band method

The FDA has concerns regarding the scientific validity of

the pressure band method because of the following technical

issues:

1. Patients with atrial fibrillation can have a very

significant beat-to-beat variation in blood pressure

depending on the length of time between ventricu-

lar systolic contractions. As a result, these patients

can have very wide pressure bands. In the FDA’s

experience with this methodology, fairly wide

pressure bands have been observed, up to almost

60 mm Hg wide, for patients with (or without)

atrial fibrillation.

2. The upper and the lower edges of the systolic (or

diastolic) pressure band are the 2 readings that define

the maximum and the minimum of the systolic (or

diastolic) pressure readings recorded by the intra-

arterial reference device during the 10-second

recording session. Thus, the pressure band method

uses only 2 readings to represent all the systolic (or

diastolic) values recorded by the invasive reference

device during this period. Hence, the method ignores

information embedded in all the remaining systolic

(or diastolic) data points. By comparison, a mathe-

matical average of all systolic (or diastolic) data

points gathers information from all such points.

Intuitively, methods of evaluation that limit the use

of available data are less optimal than those methods

that incorporate all existing data for analysis.

3. Furthermore, the FDA recognizes that single data

points are susceptible to error that is attributable to

bnoise.Q In this case, any noise interference on the

maximum or minimum data point defining the

pressure band, recorded by the reference device,

will likely increase the width of the pressure band

due to the existence of other data points inside the

pressure band, thus resulting in more zero differ-

ence scores.

The consequence of allowing a wide pressure band is that

the NIBP monitor would appear to be more accurate than

the clinical data currently support and demonstrate.

The FDA believes that there is some merit to the pressure

band method if the width of the pressure band is not

excessive. However, the FDA is not ready to propose a

specification for an acceptable width of the pressure band at

this moment, given the current lack of a broad-based

consensus regarding an appropriate pressure bandwidth.

Hence, we have contacted representatives of the AAMI

Sphygmomanometer Committee to express the agency’s

concerns with this methodology and to engage the com-

mittee to develop appropriate alternative testing strategies. It

is anticipated that many such contacts will need to take

place to develop a broadly supported performance standard

that is agreed to by the industry, the clinical community, and

the FDA.

In the interim, the FDA advises the manufacturer that the

use of the pressure band method in validating NIBP

monitors will be reviewed on a case-by-case basis.

4. Conclusion

The FDA attempts to use accepted consensus standards

whenever appropriate to lessen the burden of device

manufacturers in performing multiple different validation

tests to comply with differing technical standards. However,

as discussed in this article, there are instances in which the

agency cannot accept the use of a consensus standard. For

example, if provisions of a technical standard conflict with

Federal regulations, the agency is mandated to follow the

regulation. Another reason why the agency may not accept a

consensus standard is that there may be specific scientific

concerns regarding provisions of the standard. In all such

cases, the FDA provides a supplementary information sheet

to clearly specify the agency’s requirements when there are

differences with a technical standard.

The FDA understands the many advantages to be gained

in technological innovation and product development by

having the FDA’s regulatory requirements and international

consensus standards as harmonized as possible. To achieve

this goal, the FDA sends representatives to participate in

various standards development committees’ work. Although

this has been helpful in moving toward the goal of har-

monizing standards, the FDA realizes that much of the

work toward the development of standards by committee

must be determined by consensus via balloting, meaning

that there might be rare occasions in which there is dis-

cordance between the FDA’s requirements and the consen-

sus standard that develops. However, the FDA remains

committed to working toward a goal of harmonization of

standards whenever possible within the scope of the

agency’s regulations.