15

Buy the Book >>

Global Medical Device Regulatory Strategy

1
Use of Standards in Medical 2
Device Global Regulatory Strategy 3
4
Updated by Susumu Nozawa, RAC, FRAPS 5
6
Introduction medical device type, i.e., implantable, and the 7
At the most basic level, standards are docu- materials from which the device is made.
ments providing requirements, specifications,
guidelines and characteristics that can be used
Second, there is no one centralized listing,
database or decision tree to determine the stan- 8
to ensure materials, products, processes and dards to which a manufacturer needs to conform
services consistently are fit for their purpose. for a particular medical device’s development 9
The International Electrotechnical Commission and regulatory approval. Relevant standards
(IEC) defines “standard” as a: can vary among regulatory authorities. Many
relevant standards are written specifically for the
10
“Document, established by consensus
medical device industry, while others are written
and approved by a recognized body, that
provides for common and repeated use, generically to apply across industries, e.g., ship 11
guidelines or characteristics for activities testing standards. Such standards are relevant to
or their results, aimed at the achievement both medical device manufacturers and regula- 12
of the optimum degree of order in a given tors because they provide requirements that can
context.”1 be used consistently to ensure the device is fit for
its intended use. More frequently used standards
13
Within the context of medical device develop- are discussed in this chapter.
ment, using standards helps provide consistency Standards are not maintained by one orga- 14
in both how a medical device is developed and nization. Many organizations issue standards
the performance and expected results for cer- used in medical device development and regula-
tory approval. This chapter provides an overview
15
tain, typically established, medical device types.
Standards’ compliance may lead to faster regula-
tory approval and, for some countries, compliance
of the largest standards development and main-
tenance participants. Standards change over 16
with certain standards is required. Thus, there is time; some are revised, while others become
a strategic advantage to understanding standards obsolete and are replaced. Further, since there is 17
and their role in the medical device development no centralized body issuing standards, it can be
and regulatory approval process.
Navigating standards’ complexity can be
difficult to keep up with the various revisions,
especially in the middle of the product develop-
18
ment or regulatory submission process.
confusing to both medical device development
and approval process newcomers and veterans. Another difficulty, in most instances, is 19
First, there are different types of standards: these standards organizations are separate from
process standards and product standards. The regulatory agencies. While regulatory agencies, 20
process standards provide guidance on medical such as the US Food and Drug Administration
device development and numerous manufactur-
ing and assessment processes. Product standards
(FDA), recognize certain standards and stan-
dards’ clauses, this recognition often lags
21
generally provide desired results and testing and behind the effective date of new revisions for
assessment means, specific to such factors as the certain device classes. Each regulatory agency 22

217
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

may recognize different standards or different wishes to use a national standard of a country
standards’ revisions, thus the list of standards other than the US for US market clearance or
to which a manufacturer must adhere varies approval, it may discuss the plans with FDA
among jurisdictions. If a product is intended for in the presubmission process. In contrast, the
multiple jurisdictions, regulatory professionals EU Medical Devices Regulation (EU MDR) and
should start by researching common and similar directives in other industrial sectors, rely on
requirements simultaneously applicable to each. “harmonized” European Norms (EN) or stan-
To meet regulatory expectations, stan- dards. Those standards are prepared in response
dards are not standalone documents, may be to a mandate from the European Commission
referenced or accepted by various regulatory (EC). They are intended to be used to demon-
authorities around the world and must be strate conformity to the essential requirements
viewed in parallel with local regulations. An in one or more directives and are developed
entity dedicated to creating standards is called by the European standardization bodies, the
a standards development organization (SDO). European Committee for Standardization
Standards developed by an SDO are intended to (CEN), European Committee for
be voluntary and, as such, do not aim to replace Electrotechnical Standardization (CENELEC)
local regulations. This is the reason certain regu- or European Telecommunications Standards
latory authorities may determine standards will Institute (ETSI). Notices on the standards are
be mandatory in their jurisdictions; this type published in the EU Official Journal. Use of
of determination, however, is uncommon. On these voluntary standards confers a presumption
certain occasions, for certain jurisdictions, even a of conformity with the directives’ mandatory
widely used standard may not address a medical regulatory requirements.
device’s safety and performance concerns ade- In Australia and some countries in Asia
quately. An example of this is FDA’s Guidance on and South America, the extent to which a
Radio Frequency Wireless Technology in Medical standard is accepted or recognized may vary
Devices.2 This guidance states the IEC 60601- by local law. For example, in China, foreign
1-2 consensus standard did not address wireless manufacturers may submit a notarized quality
technology electromagnetic compatibility system certificate of compliance to a standard,
(EMC) adequately at the time the final guidance such as ISO 13485 Medical Devices—Quality
was issued in August 2013. A manufacturer Management Systems—Requirements for
intending to seek market approval in multiple Regulatory Purposes or FDA’s Quality System
jurisdictions should consult international stan- Regulation (QSR), to the China’s National
dards and local regulations in parallel. Medical Products Administration (NMPA).
In the US, a ‘consensus standard’ is one It is possible the Chinese version lags behind
developed by an SDO using the consensus the international version. In this case, the
developing process, while a ‘recognized consen- manufacturer has to demonstrate compliance
sus standard’ is a standard FDA has evaluated with the Chinese standard and provide the
and recognized for use and published in the necessary test reports. IEC 60601-1 second and
Federal Register. The consensus developing third editions may serve as another example; a
process is described later in this chapter. If a manufacturer would need to meet second edi-
manufacturer chooses not to comply with cer- tion test report requirements in China, while
tain sections of a recognized consensus standard in much of the rest of the world, it would in
when compliance with the standard is expected fact meet third edition test reports. The Brazil
(i.e., if the standard is referenced within an Good Manufacturing Practice (BGMP) is
FDA guidance document), the regulatory sub- similar to ISO 13485 per Brazilian Resolution
mission should justify the deviation and provide RDC 185/2001; therefore, a certificate of com-
the alternative used. A manufacturer must pliance to ISO 13485 may be acceptable. It is
understand the risks it takes by not complying important for regulatory professionals to consult
with applicable standards. If a manufacturer with local regulatory agencies to understand

218
 Global Medical Device Regulatory Strategy

1
which international standards and editions are
currently accepted and whether backward com-
Then, the numbering changes as various regu-
latory bodies in different jurisdictions adopt the
2
patibility is accepted.
To summarize, the use of standards to
standard to meet their specific requirements.
EN ISO 13485:2016 is the version of ISO 3
demonstrate medical device regulation confor- 13485:2016 adopted by one of the pan-Eu-
mity differs among countries. These differences ropean standard bodies, CEN, CENELEC 4
pose a challenge to the medical device regula- or ETSI. CEN, CENELEC and ETSI are
tory professional in developing a global medical
device regulatory strategy. Fortunately for the
recognized officially by the EU. Official EU
recognition means these organizations may
5
medical device industry, multiple SDOs create adopt European Norms (EN) that can become
standards deemed to offer the presumption of candidates for harmonization (recognition) in 6
conformity to specific regulatory safety and per- Europe under the directives. Appendices were
formance requirements, and these documents, added to indicate the aspects of the EU Medical 7
as mentioned earlier, usually are the recognized Devices Directive (EU MDD) the standards
standards.3 Manufacturers may rely on docu-
ments published by the International Medical
satisfy. CAN/CSA-ISO 13485:16 is the ISO
13485:2016 version adopted by the Canada 8
Device Regulators Forum (IMDRF), which National Standard/Canadian Standards for
make multiple normative references to numerous use in Canada. DS/EN ISO 13485:2016 is the 9
medical device standards. A later section in this version adopted by Denmark’s Dansk Standards
chapter discusses IMDRF’s work in more detail. Association,4 the same version approved by the
European Committee for Standardization as
10
Understanding Standards Numbering EN ISO 13485:2016 without any modifications.
Many regulatory professionals find standards’ While some regulatory jurisdictions 11
versioning or numbering confounding and, when include the year of adoption, some jurisdictions
dealing with standards, the numbering system do not, such as CAN/CSA-ISO 13485:03. 12
indeed can be so. For example, one of the most Reviewing the adopted version’s scope is nec-
well-known standards in the medical device
industry is ISO 13485. An internet search of
essary to understand which standard version
was adopted. For example, ISO 13485 was
13
“ISO 13485” could yield the following results: revised in February 2016, and various standard
• ISO 13485:2016 bodies went through their adoption process. 14
• EN ISO 13485:2016 There was a three-year transition period for ISO
• CAN/CSA-ISO 13485:16 13485:2016; thus, it is necessary to understand
the revision to which manufacturing organiza-
15
• DS EN ISO 13485:2016

Now, the question is what are the differences?

tions will comply.
16
To answer this question, start with the base Standards Developing Organization
document: ISO 13485:2016. In general, the (SDOs) 17
structure followed is: As defined earlier, an SDO is an organization
• ISO 13485:2016
o the preceding letters indicate the
dedicated to developing standards. Several 18
SDOs support the medical device industry;
issuing organization; in this case,
the International Organization for
therefore, it is important for a regulatory pro-
fessional to know who they are and understand
19
Standardization (ISO) why they exist.
o 13485 is the standard number An SDO provides consumers, industries 20
o 2016 is the revision year, some- and governments a platform to discuss and
times using only the last two
numbers
develop international standards. Each SDO, 21
when appropriate, cooperates with another and
its stakeholders to produce joint publications,
help promote the importance of standardization
22

219
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

globally, coordinate any potential overlaps in work governing the consensus standards development
and ensure international standards are seamless process. ANSI is a founding member of ISO,
and complementary with each other. Some signif- and the ANSI Essential Requirements embrace
icant SDOs are profiled in this chapter. ISO and IEC’s globally accepted standard-
International Organization for ization principles. As the US member body of
Standardization (ISO): ISO develops and ISO, ANSI accredits US Technical Advisory
publishes international standards.5 Created in Groups (TAGs). US TAGs, through ANSI,
1947, ISO is an independent, nongovernmental promote the use of US standards, policies and
organization with 164 member countries. Each technical positions internationally and advo-
member has a national committee representing cate the adoption of international standards
ISO in its country. For example, the American as US national standards when they meet the
National Standards Institute (ANSI) represents healthcare community’s needs. Because ANSI
ISO in the US. Through ANSI, the US par- is a leader in ISO’s governing body and an IEC
ticipates heavily in ISO technical committees participant, via the US National Committee,
(TC), such as ISO/TC 194 Biological and the US has immediate access to both the ISO
Clinical Evaluation of Medical Devices. ISO/TC and IEC standards development processes. As
194 is responsible for publications such as ISO the accreditor of US voluntary consensus SDOs,
10993 Biological Evaluation of Medical Devices ANSI ensures SDOs maintain integrity in
and ISO 14155:2011 Clinical Investigation developing American national standards.
of Medical Devices for Human Subjects—Good Clinical and Laboratory Standards
Clinical Practice series. The British Standards Institute (CLSI): CLSI, successor to the
Institute (BSI) represents ISO in the UK. ISO National Committee for Clinical Laboratory
representatives in specific jurisdictions can be Standards, exists to develop applicable clin-
found on the ISO members’ web page.6 ical and laboratory consensus standards and
International Electrotechnical guidelines for clinical laboratories and promote
Commission (IEC): IEC prepares and pub- their use globally.8 CLSI is accredited by ANSI
lishes international standards for electrical, and actively promotes global harmonization of
electronic and related technologies, known clinical laboratory testing standards through
collectively as electrotechnology.7 IEC mem- its participation as the Secretariat of ISO TC
bers are called national committees (NCs) who 212, Clinical Laboratory Testing and In Vitro
represent all electrotechnical standardization Diagnostic (IVD) Test Systems. CLSI also
concerns and conformity assessments in their serves as the administrator for the US TAG
countries. IEC’s objective is to promote interna- for ISO TC 212. The CLSI consensus process
tional cooperation on all questions concerning includes stakeholder experts from industry,
standardization in the electrical and electronic government and healthcare professions, gather-
fields. IEC publishes international standards, ing to develop standards for improved clinical
technical specifications, technical reports, pub- laboratory testing quality, safety and efficiency.
licly available specifications (PAS) and guides, An example of a CLSI published guideline is
and collaborates closely with ISO. The US par- Point-of-Care IVD Testing, providing guidance
ticipates through ANSI in the medical device to IVD device users outside a clinical laboratory
standards development subcommittees (SCs). setting on how to ensure results are comparable
American National Standards Institute to those obtained in laboratories.
(ANSI): ANSI is a private, nonprofit entity Underwriters Laboratories (UL): In
coordinating and administering the US vol- addition to these organizations, other SDOs
untary standards and conformity assessment exist that either publish technical standards in
systems. ANSI, itself, is not an SDO but accred- a wide range of industries or collaborate with
its SDOs that adhere consistently to the ANSI ISO and IEC in standards development and
Essential Requirements for openness, balance, publications. UL develops a wide variety of
consensus and due process, a set of procedures standards to measure and validate performance,

220
 Global Medical Device Regulatory Strategy

1
environmental health and sustainability.9
Standard UL 60601-1 Medical Electrical
medical imaging, the Medical Imaging and
Technology Alliance (MITA) plays key roles.
2
Equipment, Part 1: General Requirements for
Safety references 36 additional UL standards
MITA, a division of NEMA, is the organization
for medical imaging equipment, radiopharma- 3
that may be used in lieu of IEC 60601-1 if the ceutical manufacturers, innovators and product
differences in the two documents’ particular developers. MITA is the Secretariat of Digital 4
requirements are recognized and understood for Imaging and Communications in Medicine
effective implementation in a global regulatory
strategy. It is important to note, however, many
(DICOM). MITA technologies include com-
puter tomography (CT) scanners, nuclear
5
UL standards are not recognized by regulatory imaging, radiopharmaceuticals, magnetic res-
authorities outside the US. onance imaging (MRI), imaging information 6
Institute of Electrical and Electronics systems, ultrasound and medical X-ray equip-
Engineers (IEEE): Other professional organiza- ment. Examples of standards include NEMA 7
tions’ work includes coordinating and publishing XR 26-2012 Access Controls for Computed
technical standards or models the medical device
industry may utilize. IEEE is a professional
Tomography—Identification, Interlocks and
Logs and NEMA MS-10-2010 Determination 8
association dedicated to advancing technolog- of Local Specific Absorption Rate (SAR) in
ical innovation. IEEE, among other services, Diagnostic Magnetic Resonance Imaging (MRI). 9
publishes engineering technical standards and Other areas NEMA covers, in addition to med-
models. Medical device software engineering
professionals and software medical device and
ical imaging, include building systems, building
infrastructure, lighting systems, industrial prod-
10
mobile medical app (MMA) manufacturers ucts and systems, utility products and systems,
continue to draw from well-established IEEE transportation systems and manufacturers and 11
standards, such as IEEE 1012-2012 Standard for installers of durable medical equipment.
System and Software Verification and Validation. ASTM International: Formally known as 12
Association for the Advancement of the American Society for Testing and Materials,
Medical Instrumentation (AAMI): AAMI
is a nonprofit organization founded in 1967
ASTM International currently has more than
7,000 standards that have been adopted as the
13
supporting the healthcare community in devel- basis of national standards or referenced in reg-
oping, managing and using safe and effective ulations around the world in a wide variety of 14
medical technology. AAMI’s standards program industries. These technical standards are used
consists of more than 100 technical committees
and working groups that produce standards,
in product development, product testing and
quality systems.11 Examples of standards include
15
recommended practices and technical informa-
tion reports for medical devices. Standards and
ASTM F2516-07 Standard Test Method for
Tension Testing of Nickel-Titanium Superelastic 16
recommended practices represent a national Materials and ASTM F1980-07(2011) Standard
consensus and many have been approved by Guide for Accelerated Aging of Sterile Barrier 17
ANSI as American National Standards. AAMI Systems for Medical Devices.
also administers a number of international ISO
and IEC technical committees as well as US Additional Related Organization
18
TAGs.10 An example of an AAMI standard
is AAMI ANSI HE75:2009(2013) Human
As noted earlier, IMDRF is the successor to the
Global Harmonization Task Force (GHTF). 19
Factors Engineering—Design of Medical Devices. IMDRF is not an SDO but is an international
National Electrical Manufacturers group of volunteers representing medical 20
Association (NEMA): NEMA represents device regulatory authorities from Europe, the
nearly 325 electrical equipment and medi-
cal imaging manufacturers that make safe,
US, Canada, Japan and Australia who develop
medical device and IVD guidance documents.
21
reliable and efficient products and systems The Asian Harmonization Working Party
serving seven major markets. For standards for (AHWP),12 ISO and IEC joined IMDRF as 22

221
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

liaison members in 2012. AHWP represents 26 Using Standards to Demonstrate

member economies.13 Conformity With Regulatory
IMDRF’s purpose is to continue GHTF’s
work, producing a series of guidance docu-
Requirements
While differences in medical device regulations
ments describing a risk-based regulatory model
exist across jurisdictions, a regulatory profes-
to ensure medical device safety, effectiveness,
sional may apply international standards to
performance and quality. These guidance
demonstrate conformity to essential regulatory
documents are intended to harmonize docu-
elements to help get the manufacturer’s tech-
mentation and procedures on basic regulatory
nologies and treatments to patients faster. In the
practices used to assess whether a medical
US, international standards often are referenced
device conforms to applicable regulations in
in FDA guidance documents. When developing
each jurisdiction. These harmonized documents
a strategy, the regulatory professional is advised
and procedures are aimed at reducing, if not
to reference and implement these standards in
eliminating, differences among jurisdictions,
parallel with guidance documents to meet FDA
thereby decreasing the regulatory compliance
requirements, specifications and guidelines to
costs and allowing patients earlier access to new
ensure the medical device is fit for its intended
technologies or treatments. IMDRF guidance
use. For example, by utilizing the internation-
documents reference standards,14 such as those
ally recognized ISO 14971 Risk Management
developed and disseminated by ISO and IEC,
standard, a manufacturer can demonstrate
a regulatory professional can implement both
conformity with medical device risk manage-
within a global regulatory strategy and through-
ment requirements. ISO 14971 is referenced
out the medical device’s lifecycle.
in numerous FDA guidance documents,
Following is an example of how a global
including Guidance for Industry and Food and
regulatory professional may benefit from under-
Drug Administration Staff: Content of Premarket
standing IMDRF’s work. A manufacturer has
Submissions for Management of Cybersecurity
identified Australia as a potential target market
in Medical Devices and Factors to Consider
for its medical device and asked its global reg-
When Making Benefit-Risk Determinations in
ulatory executive to determine market access
Medical Device Premarket Approval and De Novo
requirements. Since Australia was a founding
Classifications, which addresses the intersection
IMDRF member and contributed to the guid-
of the guidance with ISO 14971 in great detail.
ance document, many standards referenced in
As mentioned earlier, the IMDRF guid-
IMDRF documents are accepted, even if cer-
ance documents also reference standards,
tain versions are not recognized, by Australia’s
such as ISO 14971. A regulatory professional
Therapeutic Goods Administration15 (TGA).
developing a medical device global regulatory
By examining IMDRF documentation, a regu-
strategy, must apply local guidance document
latory professional will be able to determine the
recommendations, reference standards and reg-
list of applicable standards for premarket evalu-
ulations to increase chances of getting medical
ation, assessment and implementation.
technology to patients faster.
The same principle applies for market
A standard is not a regulatory agency’s
access in the other IMDRF founding econ-
recommendation or guideline presented in a
omies of the US, Japan, Canada and AHWP.
guidance document. A guidance document,
Guidance documents published by IMDRF
such as the FDA’s General Principles of Software
may help a medical device global regulatory
Validation; Final Guidance for Industry and FDA
professional determine reference standards to
Staff, contains suggested regulatory guidelines
be used as part of the conformity assessment
and reflects the agency’s current thinking and
process to meet different countries’ regulatory
recommended best practices for the medical
requirements.
device regulatory process. Like IMDRF docu-
ments, FDA guidance documents may reference
numerous process, safety and performance

222
 Global Medical Device Regulatory Strategy

1
standards, such as those developed and dissemi-
nated by ISO and IEC.
Figure 15-1. Document Hierarchy
2
A standard is a not a regulation. A regu-
lation is a national rule implementing a law, 3
which, if violated, can result in a penalty. A Laws
national regulatory body develops a regulation.
Regulations
4
Figure 15-1 presents a graphic representation
of the hierarchical relationship between reg-
ulations, guidance documents, standards and
Guidances 5
technical reports. It is important to remem-
ber regulatory agencies issue regulations and
Standards
6
guidance documents, while SDOs, which are Technical Reports
nongovernmental entities, issue standards and 7
technical reports.

Product Standards and Process 1,000 standards are used in the medical device 8
industry, a few are worth profiling in this chap-
Standards
Standards can be grouped into three major
ter due to their broad usage and recognition. 9
These profiled standards, recognized and
categories: compatibility, process and safety and
performance. Universal serial bus (USB) and
referenced by multiple regulatory authorities
and generally applicable to all medium- to
10
blue-ray disc standards are specific examples of
high-risk medical devices, include ISO 13485,
compatibility standards. Process standards cover
a medical device product’s lifecycle. Process
ISO 14971 and IEC 62366 Medical Devices— 11
Application of Usability Engineering to Medical
standards dictate a process or overall system’s
requirements but do not dictate how a medical
Devices. IEC 62304 Medical Device Software—
Software Life Cycle Processes will be profiled and,
12
device manufacturer should meet these require-
ments. Standards also can be categorized as
as the title indicates, is applicable to medical
devices containing software, standalone software 13
vertical, collateral or horizontal. For medical
or mobile medical applications. Last but not
devices, horizontal standards would be “gen-
eral” standards applicable to almost all medical
least, ISO 14155:2011 Clinical Investigation 14
of Medical Devices for Human Subjects—Good
devices. For example, ISO 13485 Quality
Systems, ISO 14971 Risk Management and ISO
Clinical Practice, also will be profiled in this
chapter, since clinical investigation is a critical
15
15223 Symbols for Labelling would apply to
process by which a manufacturer collects safety
most regulated medical devices. The collateral
standards would be “group” standards applicable
and performance data to support medical device 16
market approval.
to certain type of products. Examples would be
IEC 60601-1-2: Electromagnetic Disturbances: 17
Requirements and Tests and IEC 60601-1-3 ISO 13485—Medical Devices—Quality
Radiation Protection in Diagnostic X-Ray Management Systems—Requirements for 18
Equipment. In contrast, vertical standards apply Regulatory Purposes
to specific devices or device categories, such as
the IEC 60601-2 family of standards that apply
ISO 13485 gives available quality management
system (QMS) requirements an organization can 19
to certain electromechanical medical devices. use for medical device design and development,
SDOs and professional associations have production, installation and servicing and design- 20
developed and published numerous compat- ing, developing and providing related services.16
ibility, process and safety and performance ISO 13485 is derived from historic versions
of ISO 9001 (versions prior to 2015), a standard
21
standards. Only standards relevant to the medi-
containing QMS requirements used around the
cal device lifecycle, from concept to market, are
within this chapter’s scope. While more than world for various manufacturing and service 22

223
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

industries.17 ISO 13485 and ISO 9001 are mov- ISO 13485 includes general QMS require-
ing farther apart: however, as ISO 9001 evolves ments, management’s overall QMS responsibility,
into a true ‘quality system.’ In the past, most of resource management (both human and physical
the ISO 9001 clauses, subclauses and format resources), product realization and measurement,
were identical to those in ISO 13485, but this analysis and improvement.
has changed to facilitate understanding of the In the US, FDA stipulates a manufacturer
differences. The latest edition of the ISO 13485 (domestic or importer) must have a QSR-
has Tables B.1 and B.2 in its Annex B to show compliant QMS. The QMS standard, ISO
the correspondence between ISO 13485:2016 13485, was first adopted in the US as ANSI/
and ISO 9001:2015. AAMI/ISO 13485:2003. Although ISO 13485
For most jurisdictions, including the EU, and QSR elements are similar, they are not
Australia and Canada, the preferred method to identical. A manufacturer may need to fulfill
prove conformity with regulatory requirements certain obligations to comply with the QSR that
is certification of the manufacturer’s QMS to are not part of ISO 13485. One example is the
ISO 13485. In December 2018, FDA formally QSR requirement to use statistical techniques
announced its intention to transition away not specified in ISO 13485.
from the Quality Systems Regulation (QSR) At the time of writing this chapter, ISO
per 21 CFR Part 820 and transition to ISO 13485:2016 is not officially recognized by the
13485:2016 for its audit inspections of medical EU Commission. Upon publication, the man-
device manufacturers.18 FDA stated that “We ufacturer must review the gap between the
recognize there will be a significant impact harmonized standard and EU MDR require-
on FDA for implementation. For example: ments to ensure compliance.
Training on ISO 13485 requirements, interpre- Despite these differences, using ISO 13485
tation, best practices, etc. to CDRH staff and still can streamline QMS establishment to meet
ORA investigators and compliance officers. the majority of regulatory agency requirements
Changes to the inspection model (QSIT). around the world. It is worth noting here links
Revisions/updates to numerous documents. exist between other standards and ISO 13485.
Changes to IT systems. Transition period will How ISO 13485 outlines the basic manufac-
likely be a few years.”19 turer QMS framework was described earlier.
The 2016 revision for ISO 13485 placed However, other process standards less overarch-
more emphasis on QMS across the entire ing than ISO 13485 exist that help frame QMS
supply chain and is intended to address the subprocesses or subsections. Examples include
total product lifecycle of medical devices, ISO 14001 Environmental Management Systems
among other changes to the previous edition. and ISO 14971 Risk Management.
In March 2019, FDA discontinued accepting
Declaration of Conformity to ISO 13485: 2003 ISO 14971 Medical Devices—Application
for regulatory purposes and confirmed that ISO of Risk Management to Medical Devices
13485:2016 should be used instead. ISO 14971 specifies the process to identify
As described previously, process standards hazards associated with medical devices, to esti-
largely are nonprescriptive: the requirements are mate and evaluate and control those risks and
presented, but how to meet those requirements monitor the controls’ effectiveness throughout
is not specified. The standard recognizes a wide the product lifecycle.20 It is referenced in ISO
variety of medical devices (from simple and low- 13485 and numerous other standards, as the one
risk to complex and high-risk) are developed by in which guidance related to risk management
a multitude of organizations (from small start- during product realization may be found.
ups with small staffs to large, multi-national To emphasize, this standard outlines the
corporations with thousands of employees); thus, risk management process but does not prescribe
processes successful for one organization will not the specific hazards and risks to be mitigated
be the same as those for another. and controlled for each medical device type.

224
 Global Medical Device Regulatory Strategy

1
Given the wide range of medical devices, from
thermometers to surgical tools, and the technol-
use-associated risks. Similar to other standards
discussed previously, and for similar reasons,
2
ogies in use, an encyclopedia of hazards and risk
mitigation measures would be large, unwieldy
IEC 62366 does not prescribe the specifics of a
medical device user interface, but does describe 3
and out-of-date as soon as it was published. the analysis, specification, design, verification,
The range of risks varies from device to device and validation usability processes related to 4
depending on the technology used, its intended device safety. The standard has close ties and
use and its method of use. For example, dental
hygienists use tools such as scalers and hand
many references to ISO 14971. If designed well,
a manufacturer’s risk management and usabil-
5
instruments to scrape bacterial deposits from ity processes will dovetail efficiently into each
teeth. Micro-ultrasonic scalers also are avail- other. One IEC 62366 appendix includes a dia- 6
able for the same purpose—removing bacterial gram mapping the inputs and outputs between
deposits—but use vibration and a pressurized risk management and usability processes. 7
stream of water. The risks of the simple hand
tool scaler are much different than those of the
micro-ultrasonic scaler.
IEC 62304 Edition 1.1 2015-06 Medical
Device Software—Software Lifecycle
8
As technologies evolve, new hazards will be Processes
introduced that may not be foreseen; thus, there Software is incorporated into many medical 9
is a need for a standardized risk identification, devices. Just as it is necessary to ensure safe
mitigation and control process.
The general process outlined by ISO 14971
and effective mechanical and electromechan- 10
ical devices, devices incorporating software
creates a risk management plan to document
how risk management activities will be per-
also must be safe and effective. This standard
was created in the belief that software testing
11
formed. The next step is risk assessment to alone is insufficient to ensure safe operation.
identify potential hazards and estimate the risk Thus, IEC 62304 provides a framework for safe 12
for each situation associated with the potential software design and maintenance processes
hazards. In the example of the scaler hand tool,
the sharp tip presents a potential hazard.
throughout the product lifecycle. It assumes 13
software activities occur within a QMS and risk

IEC 62366-1 Usability in Medical Devices

management system, specifically ISO 14971.
This standard includes general requirements 14
As healthcare and technology have progressed for software development, maintenance, risk
over time, more-complicated medical devices management, configuration management and 15
and device use by less-skilled users, including problem resolution processes. Similar in nature
patients themselves, have followed suit.21
IEC 62366 was published in 2007 and
to the standards cited above, this standard does
not prescribe what software code should look
16
amended in 2014, expanding the standard’s like but focuses on the processes to create safe
scope to include all medical devices, nonac- and effective software. 17
tive implantable medical devices and active ISO 14971 is referenced in several of the
implantable medical devices. More recently, IEC
62366 was revised in 2015 to IEC 62366-1. The
standards mentioned above. Sometimes, an SDO 18
publishes a Technical Report (TR) to guide
updated standard divides IEC 62366 into two
parts: IEC 62366-1 and IEC/TR 62366-2. The
a manufacturer or regulatory professional in
applying a certain standard. IEC TR 80002-1—
19
first part discusses usability engineering princi- Medical Device Software—Part 1: Guidance on
ples and provides an overview of how usability is the Application of ISO 14971 to Medical Device 20
incorporated into medical device development. Software is one example. This TR is the result of
The second part is a technical report including
guidance on compliance with IEC 62366-1.
collaborative work by joint working groups IEC 21
SC 62A Common Aspects of Electrical Equipment
This standard addresses the need for usabil-
ity engineering to minimize use errors and
Used in Medical Practice, IEC 62 Electrical
Equipment in Medical Practice and ISO TC 210 22

225
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

Quality Management and Corresponding General is to enable an easier approval process with
Aspects for Medical Devices. IEC TR 80002-1 is regulatory bodies. Standards are voluntary
extremely helpful in understanding how to apply but, in some jurisdictions, have a particular
risk management principles in ISO 14971 to regulatory status and are recognized as a (the)
medical device software. preferred means by which the manufacturer
may demonstrate conformity with the manda-
ISO 14155:2011 Clinical Investigation of tory regulatory requirements. Thus, it generally
Medical Devices for Human Subjects—Good is easier to conform to the standard instead of
Clinical Practice providing justification for not using it.
ISO 14155 is intended to ensure Good Clinical Standards play an important role through-
Practice (GCP) is followed during a medical out the medical device lifecycle. Various
device clinical investigation to ensure subject standard types exist to support all involved
safety. medical device products and processes, such
ISO 14155 details the baseline clinical as risk management and quality systems.
investigation requirements for market approval Multiple medical device industry stakehold-
safely. Key stakeholders, e.g., the sponsor and ers are involved in developing standards and
principal investigators, are required to follow stay involved in updating them as necessary.
the standard’s requirements. Recognized by Standards help harmonize regulatory processes
FDA, ISO 14155 can be applied in parallel with to ensure medical devices’ safety and perfor-
FDA’s GCP and guidance on an investigational mance are not compromised at any point during
device exemption (IDE); however, it should their lifecycle, playing an important role during
be noted, while consistent with FDA’s GCP medical device and diagnostic product confor-
requirements, conformity with ISO 14155 alone mity assessments.
is insufficient for US clinical investigations. As mentioned above, various standards
Further, conformity with ISO 14155 may not exist to support medical device processes and
be sufficient for FDA to accept data from clin- can help manufacturers streamline their risk
ical investigations conducted outside the US. A management processes. Standards generally are
medical device global regulatory professional established to promote consistency and best
must understand the common principles in all practices leading to devices meeting current
these documents are pertinent when a medical safety and effectiveness state-of-the-art expec-
device is investigational, i.e., undergoing safety tations. Designing to a standard can mitigate
and performance evaluations, under applicable potential application (use) and design risks.
laws and GCP. For example, a device’s electrical power results
Some of the additional normative stan- in risks associated with shock hazards. UL
dards referenced in ISO 14155 are ISO 13485, 60601-1 Medical Electrical Equipment, Part 1:
ISO 10993, ISO 15223 Symbols to be Used With General Requirements for Safety, outlines stan-
Medical Device Labels, Labeling and Information dards for electrical safety protection methods;
to be Supplied, Part 1—General Requirements designing a device to comply with this standard
and EN 1041 Information Supplied by the can be documented as mitigation measures
Manufacturer of the Medical Device. A regulatory taken for shock hazard risks. This documenta-
professional must not assume; however, that tion also can support ISO 14971 requirements,
normative references in a standard are recog- the medical device risk management standard.
nized automatically. In the US, FDA’s guidance, Center for
Devices and Radiological Health (CDRH)
Standard Operating Procedures for Identification
Benefits of Using Standards
of Candidate Consensus Standards for Recognition,
The Standards and Conformity Assessment provides an established process for standards’
Program22 recognition.23 A Standards Task Group (STG),
A key reason for complying with standards and reporting to the Standard Management Staff
integrating them into product development

226
 Global Medical Device Regulatory Strategy

1
(SMS), is responsible for coordinating all
CDRH consensus standards’ activities within
confidence in medical device testing, which
should decrease the need for internal FDA
2
its assigned technical area with relevant SDOs.
The recognition process begins when an STG
consultations, complete test report reviews and
additional information requests for standards 3
identifies an existing and needed standard that are part of the pilot program. Ultimately, the
within its technical area and prioritizes required ASCA pilot is intended to help FDA ensure safe, 4
activities per common criteria. Then, the STG effective and high-quality medical devices are
coordinates an assessment of whether the stan-
dard can be used to meet a particular premarket
available to patients without avoidable delay.25
The ASCA guidance document is expected to be
5
or statutory requirement. Upon completing the finalized in late 2020 or early 2021.
assessment, it then recommends the standard be Outside the US, several regulatory author- 6
recognized, as whole or a part, through publica- ities have processes in place to recognize
tion in the Federal Register. The Federal Register standards within their jurisdictions. Globally, 7
notice includes not only the newly recognized SDOs have established standards development
standards; it also includes modification to the
previously recognized standard and identifies
processes, described in the following section.
8
any previously recognized standard(s) that no Standards Development Process
longer will be recognized. Any medical device A ‘consensus standard’ is designated as such 9
industry stakeholder may propose a standard for because it takes all stakeholders’ interests into
recognition. The process includes submitting the
standard title, reference number, date and SDO.
consideration and defines what they have agreed. 10
Consensus is considered a general agree-
In addition, the stakeholder must list device
types to which the standard would apply and
ment, characterized by the absence of sustained
opposition to substantial issues by any import-
11
a brief identification of device testing, perfor- ant stakeholders, through a process that takes
mance and/or other characteristics a declaration all concerned parties interests into account and 12
of conformity to that standard would address. reconciles conflicting arguments. However, it
In September 2018, FDA finalized the
guidance, Appropriate Use of Voluntary Consensus
is important to remember consensus need not
imply unanimity but rather agreement to most
13
Standards in Premarket Submissions for Medical of the proposed requirements or guidelines by
Devices.24 This final guidance provides guidance to the majority of the stakeholders. Care also is 14
industry and FDA staff about the appropriate use taken to ensure a standard does not confer a
of national and international voluntary consensus
standards in the preparation and evaluation of
competitive advantage on individual operators. 15
The standardization process encom-
premarket submissions for medical devices.
In accordance with amendments made
passes standards’ development, promulgation,
implementation and compliance. While some
16
to Section 514 of the Federal Food, Drug and governmental bodies develop standards, most
Cosmetic Act by the FDA Reauthorization Act are written by nongovernmental entities, several 17
of 2017, and as part of the enactment of the of which were profiled earlier in this chap-
Medical Device User Fee Amendments of 2017,
FDA intends to implement a pilot conformity
ter. Those organizations follow a transparent 18
process open to public scrutiny, where partic-
assessment initiative, entitled the Accreditation
Scheme for Conformity Assessment (ASCA).
ipation is balanced and an appeals process is
included. Behind each medical device standard
19
This voluntary, pilot program is designed to is a comprehensive process including extensive
increase consistency and predictability in data gathering, analysis and discussion from all 20
FDA’s approach to assessing conformance with stakeholders’ perspectives and agreement on
ASCA-eligible standards in medical device
premarket reviews.
critical factors. Stakeholders, such as regulatory
agencies and IMDRF, support standards’ use
21
The ASCA pilot is intended to reduce reg- by referencing them in guidance documents
ulatory burden by enhancing product reviewers’ and publications. National regulatory authority 22

227
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

experts in some countries participate in stan- A reporting feature reports glucose trending
dards development. information in real time. The device can be
Finally, medical device SDOs rely on programmed to stop or suspend insulin delivery
standards’ sales to support their programs’ and automatically for two hours when the sensor
services’ continuous improvement. By charging detects the glucose level has fallen below a pre-
for standards, an SDO also can ensure it is not set value. The glucose sensor is inserted through
influenced unduly by a single party’s interests. the patient’s abdomen and senses or measures
glucose values. These values are transmitted to
How to Choose Medical Device the insulin pump and displayed for the patient
Standards to see. The insulin is delivered by the pump
A regulatory professional needs to consider through the infusion set.
standards from design and development Since an APDS is a complex system, the
through the medical device’s lifecycle. This is an device’s failure can cause death or serious injury;
integral part of global regulatory and clinical therefore, it falls under the highest risk classifi-
strategy, since standards help demonstrate a cation, Class III, in both the US the EU.
device’s safety, performance and efficacy to meet How are standards chosen for this device?
regulatory requirements. Fortunately, for this case study, several guidance
documents exist, including Final Guidance for
Industry and the Food and Drug Administration
Case Study: Standards’ Use in Developing
Staff: The Content of Investigational Device
a Hypothetical Artificial Pancreas Device Exemption (IDE) and Premarket Approval (PMA)
System (APDS) Applications for Artificial Pancreas Device Systems.
This case study assumes the manufacturer is Horizontal and vertical standards comprise
responsible for developing an APDS and its the body of knowledge to help a regulatory
clinical investigation approval in the US and professional choose the correct standards. In
EU. An APDS is a complex, connected IVD addition, FDA has compiled a guidance enti-
device system comprising several components, tled, Frequently Asked Questions on Recognition of
and is an excellent example of the use of verti- Consensus Standards, as a primary guide to under-
cal and horizontal standards. An APDS device standing the agency’s current thinking on how to
includes a glucose meter, an insulin pump, an identify standards applicable to a certain medical
insulin reservoir, a sensor, a display for acquired device and why to apply standards to US and EU
glucose values and a transmitter. The device also submissions.26 The device development team can
contains some complex software. This device is reference this guidance to demonstrate the device
an improvement on the traditional continuous is safe and works as intended, as can the regu-
glucose monitoring system design because the latory and clinical teams, to ensure the device is
sensor monitors cell glucose values continu- investigated to conform to local regulations and
ously and transmits these values to the insulin international standards.
pump. The device’s software allows it to be pro- A regulatory professional should start by
grammed to carry out one of three specific tasks: identifying US Code of Federal Regulations
1. deliver insulin automatically should notice(s) on Essential Requirements for medical
glucose level fall below a predefined device safety and efficacy or performance based
threshold on functionality and mode of action, intended
2. control insulin delivery based on pre- use, site of action and mode of operation. A
defined low and high thresholds search for a relevant FDA guidance document
3. control insulin delivery to a predefined would be conducted. Standards referenced in
glucose target level. the relevant guidance document then can be
selected. Using standards will help the manufac-
The meter component is designed to measure turer identify the device’s preclinical and clinical
and display glucose values continuously, so testing and critical postmarket requirements.
basal insulin may be calculated and delivered.

228
 Global Medical Device Regulatory Strategy

1
Fortunately, there is an FDA APDS guidance
document. The guidance references several
all components provided as sterile, regardless
of whether they are for single or multiple use.
2
horizontal and vertical standards. In addition,
a summary of safety and effectiveness data
ISO 11607 Packaging for Terminally Sterilized
Devices, ASTM D4169 Standard Practice for 3
(SSED) for a similar device or precedent, if one Performance Testing of Shipping Containers and
exists, may be examined. From these documents Systems and ASTM D642-00 Standard Test 4
and the referenced standards, a fairly compre- Method for Determining Compressive Resultant
hensive list of standards can be obtained that
might cover the majority of, if not all, preclinical
of Shipping Containers, Components and Unit
Loads were applied to sensor packaging. For the
5
testing requirements and bench performance manufacturer to ensure baseline packaging and
objective performance criteria, EMC, biocom- shipping requirements are met for this sterile, 6
patibility, sterility assurance, packaging, shelf single-use device, these three standards were
life, shipping, software and human factors. applied to validate the sensor is packaged for 7
The various research and development, device sterilization and protection adequately.
engineering, quality and clinical cross-functional
groups within the organization will need to
Packaging standards for device components
provided sterile, as opposed to those provided 8
ensure all regulatory requirements are met. In non-sterile differ. IEC 62366-1:2015, discussed
addition, a discussion about standards should previously, helps analyze, specify, design, verify 9
occur since standards play a significant role in and validate the device’s usability for safety.
helping establish and communicate baseline
expectations at each APDS product lifecycle
Finally, ISO 14155:2011 is applied in global
APDS clinical investigation. ISO 13485 for
10
stage. A few examples of the applicable numerous quality systems and ISO 14971 for risk man-
horizontal and vertical standards for disparate agement also would apply. 11
APDS components are discussed below. Standards cited in the discussion above are
Since the APDS insulin set component not intended to be comprehensive. This case study 12
is inserted under the patient’s skin, regulators is intended to demonstrate the breadth of stan-
would be interested in the set materials’ bio-
compatibility. Certain parts of the ISO 10993
dards applicable to a typical, complex, highest-risk
IVD device system. Identifying, understanding
13
series may be examined to understand and and applying relevant standards may help the
meet APDS biocompatibility requirements manufacturer’s cross-functional team develop 14
within a risk management process. An FDA a device that eventually will meet regulatory
blue book memo, entitled Use of International
Standard ISO 10993, Biological Evaluation of
requirements in the US and other countries. 15
Medical Devices Part 1: Evaluation and Testing,
can be consulted in parallel.27 A manufacturer
Case Study: Use of Standards in Developing
a Hypothetical Replacement Heart Valve
16
will need to provide biocompatibility testing The replacement heart valve provides another
result summaries, since the standard, itself, case study of the application of both vertical and 17
does not include pass/fail criteria. ISO 11137 horizontal standards in developing a medical
Sterilization of Health Care Products—Radiation
helps in understanding sterility testing and
device. Heart valves are high-risk devices, Class 18
III in the US28 and under the EU MDD.29
validation requirements. The device system’s
sensor component, which is a single-use dis-
Heart valves are in constant contact with the
patient’s blood and can cause death or serious
19
posable device, is intended to be inserted under injury if they fail. The widely publicized failures
the patient’s skin and remain there for up to six of the Shiley Heart Valve in the 1980s led to 20
days. In addition to the sensor, the pump, trans- heightened awareness of valves by all stakehold-
mitter, reservoir, and infusion set also are sterile
components. ISO 11137 provides baseline
ers, including doctors and patients, regulators and
manufacturers. Concerns about the Shiley Heart
21
requirements for the electron beam steriliza- Valve and other devices were factors in enacting
tion process and validation used to sterilize the Safe Medical Devices Amendment of 1990.30 22

229
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

Replacement heart valves can be made team will be expected to establish an overall
of various materials. Mechanical heart valves protocol for verifying and validating the design,
usually consist of one or two tilting discs or relying on state-of-the-art thinking about valves
“leaflets” operating inside a ring or housing. and the most appropriate available standards
The discs often are made of ceramic, such as and guidance.
pyrolytic carbon; the housings also can be made Because the manufacturer intends to study
of ceramic or a metal, such as titanium. Tissue and market the valve first in the US, the devel-
heart valves use animal-derived tissue, such as opment team should be knowledgeable about
bovine pericardium or an intact porcine valve. FDA expectations. FDA first published Draft
The tissue is treated during the manufacturing Guidance for Industry and FDA Staff, Heart
process, often with glutaraldahyde or a simi- Valves—Investigational Device Exemption (IDE)
lar fixative. Most surgically-implanted valves and Premarket Approval (PMA) Applications
also have a “sewing ring,” often of polyester, to in 1994.32 The guidance was revised and reis-
enable the surgeon to suture the prosthetic valve sued in 2010. ISO first published ISO 5840
into the patient’s native tissue annulus. Cardiovascular implants—Cardiac valve pros-
However, for this case study, assume the theses in 1996.33 The standard was revised in
device manufacturer wants to incorporate 2005 and reaffirmed in 2010. This standard
the latest technological innovations. To treat has since been revised by ISO 5830-2:2015
patients at a high risk of complications in tra- Cardiovascular Implants—Cardiac Valve
ditional open-heart surgery, the valve will be Prostheses—Part 2: Surgically Implanted Heart
delivered via a catheter. The catheter will be Valve Substitutes.34
introduced into the patient’s groin, will pass The manufacturer, then, would use guid-
through the femoral artery and up through ance documents and standards in parallel in the
the aorta. The valve then will be released from development process. ISO 5840 provides an
the catheter and fixed in place of the patient’s excellent outline of general requirements, even
native aortic valve. The valve itself will need to specifying design input, output and transfer,
be flexible and compressible to be loaded onto a and risk management.35 The standard goes on
catheter. To avoid potential risks associated with to identify further general requirements, such
tissues of animal origin, the manufacturer has as material property assessment, hydrodynamic
decided to manufacture the valve housing and performance assessment, structural performance
leaflets from a polymer material. assessment, etc., with some specific require-
The manufacturer intends to offer this valve ments defined in the annexes.
to patients worldwide and has developed a reg- The FDA guidance provides more detail
ulatory strategy to begin clinical studies in the in some areas and is intended to be compli-
US and then use those data to submit market- mentary to ISO 5840. Specific requirements
ing applications in other regulated countries.31 are identified for in vitro testing, including
The manufacturer will adhere to a rigid durability, fatigue, dynamic failure mode and
design control process that will include ade- cavitation. Similar levels of detail are provided
quate periods of time to define user needs and for preclinical animal testing, along with specific
develop design input leading to design output. recommendations on how to submit the data in
Further, the manufacturer will schedule a series IDE and PMA applications. As expected, the
of design reviews to act as gating mechanisms guidance provides a great deal of information
throughout the development process. As certain about clinical testing, including objective per-
milestones are reached during design and test- formance criteria. Finally, there is a section on
ing, these reviews will either confirm the design labeling. The appendices also provide a wealth
is meeting expectations and move activities into of detail regarding shelf life, cavitation, verifica-
the next phase, or direct the design and devel- tion of Bernoulli’s principle and a protocol for
opment team to return to the previous phase for echocardiographic assessment.
retesting or design revision. The development

230
 Global Medical Device Regulatory Strategy

1
The sponsor would develop an overall
testing protocol for the valve carefully, follow-
horizontal standards, and especially the verti-
cal standards and guidance, the manufacturer
2
ing the ISO standard and paying particular
attention to the FDA guidance. Sponsors may
is able to identify FDA and other regulators’
expectations. The manufacturer can develop an 3
elect to develop the protocols themselves or overall test protocol and even vet that protocol
contract with third-party experts to develop the with FDA through the presubmission process. 4
protocols or conduct testing. The manufacturer The sponsor can test the device and challenge
probably would want to consult with FDA prior
to commencing lengthy and expensive testing to
the results through the manufacturer’s own
design assurance process. Through the appro-
5
ensure the agency’s expectations would be met. priate and rigorous application of international
Note: FDA guidance even calls out the standards and regulatory guidance, the man- 6
presubmission process to make sponsors aware ufacturer can establish the device’s safety and
of these options.36 effectiveness and provide valid scientific evi- 7
The manufacturer would use not only the dence to support PMA approval in the US and
international standard and FDA’s heart valve
guidance but also look to a number of applicable
marketing approval in other countries.
8
horizontal standards. Because the heart valve How to Find Standards for a Medical
is implantable and, further, because the manu- Device 9
facturer has elected to use a polymer, a material Several SDOs provide search engines to locate
with limited usage in this application, the
materials’ biocompatibility will be of particular
standards. Most standards must be purchased in 10
electronic or paper form from the SDO’s web-
interest to the manufacturer and regulators. ISO
10993 provides biocompatibility testing require-
site. Many standards developers collaborate with
re-sellers authorized to market the documents
11
ments. The manufacturer also should consult on their behalf.
FDA’s final guidance on the use of ISO 10993.37 In addition to visiting SDO websites, reg- 12
Other horizontal standards would be ulatory professionals may utilize one of many
necessary in the development process to help
define requirements common to all implantable
standards search engines. These search engines 13
interface with specialized databases that aggre-
medical devices, e.g., symbols and labeling,
packaging, and sterilization. Other broad hor-
gate all major developers’ standards. One such
search engines is the ANSI-based NSSN http://
14
izontal standards critical to any development www.nssn.org/. When the key search term
process include ISO 14971 for risk manage-
ment and the ISO 13485 or QSR for QMS.
‘medical device’ is entered, a list of device-rele- 15
vant standard documents with associated titles
Finally, because this hypothetical heart
valve will be delivered by catheter, a specific
and SDOs’ names appears. Other search terms
to be considered include the device’s primary
16
part of the vertical standard, ISO 5840-
3:2013 Cardiovascular Implants—Cardiac Valve
function and application, i.e., drug delivery,
therapy, ablation. 17
Prostheses—Part 3: Heart Valve Substitutes Some regulatory authorities like FDA and
Implanted by Transcatheter Techniques, defin-
ing operational conditions and performance
bodies like the EC medical devices unit also 18
have databases a manufacturer can search for
requirements for the catheter delivery system
must be applied.38
recognized consensus standards applicable to the
device being developed. For FDA, one helpful
19
This case study illustrates, even though the method is determining potential predicate(s) for
device design output is innovative and incor- the device under development and the corre- 20
porates features uncommon or even unavailable sponding FDA product code classification (e.g.,
in some markets, the manufacturer and the
development team have an available body of
DTC is the Pacemaker Generator Function 21
Analyzer product code). FDA’s database for
knowledge based on years of experience with
replacement heart valves. Through the available
recognized consensus standards can be searched
to locate those associated with the same DTC
22

231
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

product code. In this example, two recognized particular device, the technologies it embod-
consensus standards appear: ISO 27185:2012 ies and the processes by which it is to be
Cardiac Rhythm Management Devices—Symbols to manufactured.
be Used With Cardiac Rhythm Management Device A list of key words then can be gener-
Labels and Information to be Supplied—General ated to serve as key search terms for relevant
Requirements and ISO 27185 First Edition standards using an SDO or service’s (e.g.,
2012-02-15 Cardiac Rhythm Management TechStreet or IHS Engineering Workbench)
Devices—Symbols to be Used With Cardiac Rhythm standards search engine. The resulting standards’
Management Device Labels, and Information to be lists then can be examined for specific applica-
Supplied—General Requirements. bility and narrowed further per search terms.
Note: This example also illustrates the A similar approach could be followed
importance of regulatory strategy. For many for the US, although FDA does not use the
new technologies and potential medical devices, Essential Requirements model. For the US, the
no clear predicate is on the market, but options regulatory professional would begin by reviewing
exist for combining and choosing predicates. the US CFR to identify relevant regulations for
Because the associated consensus standards vary the device. This review can be conducted using
with each predicate, this search can determine the database at http://www.ecfr.gov. FDA also
the necessary effort to bring the product to encourages manufacturers to discuss plans to use
market under various regulatory strategies. standards or any specific issues relating to use of
Since clear product or process standards standards during a presubmission meeting.
for a particular medical device may not exist, a
regulatory professional may be unable to find Case Study: A Hypothetical Magnetic Needle
specific relevant standards for a device. Typically, and Suturing Thread Device
this situation would occur if the device utilizes In this case, a regulatory professional is unable
a particularly novel technology and/or claims to locate relevant standards for a medical device
an especially innovative intended use. In such easily. The manufacturer is developing a novel
a case, standards may not be able to cover all magnetic needle and suturing thread with a
aspects of the device under development. The magnetic tip.42 The search terms based on the
earliest endovascular grafts utilized standards claimed intended use, device’s purpose, primary
for surgically implanted grafts, intravascular mode of action, Essential Requirements, tech-
catheters39 and vascular stents.40 Applicable nology and manufacturing processes could yield
sections of each of the separate standards were the following list:
incorporated into design input for the new • suture
endovascular grafts.41 Similarly, some of the • suturing
early catheter-delivered heart valves drew from • surgical needle
standards established for surgically implanted • magnet
valves and catheter delivery systems. Design • magnetized instruments
teams need to be current on standards for all • suture thread
of their devices’ design characteristics and draw
broadly from standards that may even target a Using these search terms, a list of standards is
different device type. created:
For the EU (IMDRF for Australia, Japan, • GME B 040 0367 Magnet Powder
Singapore and Canada), the device’s claimed Paste
intended use, purpose and primary intended • BS 7507 Malleable Wires for Use
mode of action must be identified first. MDD as Sutures and Other Surgical
Essential Requirements (IMDRF Essential Applications
Principles) of safety and performance must • A-A-51410 Suture, Nonabsorbable,
be reviewed to identify those relevant to the Surgical, Polypropylene,
Monofilament, Single Armed

232
 Global Medical Device Regulatory Strategy

1
A review of these abstracts may eliminate certain
nonapplicable standards. In this example, the
medical device’s state of the art; a standard
currently being used changing in the middle
2
Magnet Powder Paste standard would be elimi-
nated because the magnet will not be in powder
of medical device development or regulatory
review; subsequent revisions to existing stan- 3
paste form. The remaining standards would be dards used in the original device design process
reviewed next. Reviewing the standards’ texts is being incorporated retroactively in devices 4
recommended to determine whether all or only already in commercial distribution; and the
certain clauses would apply to device develop-
ment, evaluation and manufacturing, all critical
standard used previously being revised and
resulting in a device design change.
5
global regulatory strategy elements. It is possible, even after examining the list
It is important to remember a standard of standards for specific applicability and nar- 6
search is an iterative process dependent on the rowing it further, numerous standards appear
device development stage. A device in the con- relevant. One approach is to determine whether 7
ceptual or early development phase may change any of these standards overlap in any way or
as new features, technologies, intended uses
and/or purpose evolve. These changes, in turn,
each addresses a set of unique topics. If one
addresses performance requirements and another 8
would affect the key search term list and result- test methodologies, both would apply. If one
ing list of potential, applicable standards. addresses a set of topics (EN ISO 13485:2016) 9
and another an adoption of the same topics
Case Study: A Hypothetical APDS With a for a different jurisdiction (CAN/CSA-ISO
13485:16), the one most-aligned with the target
10
Design Change
jurisdiction should be selected. Any standard
In this case, the manufacturer is developing a
new and improved infusion pump for the hypo- on the list that is a recognized standard in any 11
thetical APDS device presented earlier in the target jurisdiction should be identified. It is
chapter. The improvement is the introduction important the regulatory professional look for 12
of a Bluetooth wireless communication device common and similar requirements applicable
utilizing artificial intelligence in an MMA,
allowing caretakers and healthcare providers to
in various target jurisdictions. A gap analysis is
recommended. The extent of commonality or
13
monitor basal insulin dosage delivery remotely. differences would impact the overall regulatory
Key search terms now could include Bluetooth, strategy greatly. If compliance with a standard’s 14
wireless communication, software medical differences in any target jurisdiction leads to
device, and mobile medical device. Once a list of significant design and development changes and,
therefore, increased time-to-market, the regula-
15
standards is generated, the manufacturer would
examine the standards for relevance and select
those matching its search criteria.
tory professional may recommend dropping the
target jurisdiction. 16
In this example, if the manufacturer intends A regulatory professional may find an
to distribute the device in the US, FDA’s pre- existing standard no longer reflects a particular 17
submission process may be utilized to discuss technology’s state of the art. Typically, there is
a standard selection plan, any specific issues a lag between a new technology’s introduction
and its general acceptance as state of the art.
18
regarding the standards used relating to the
It takes the user community and stakeholders
specific design change, etc.
several years to gain comprehensive knowledge 19
Finding Standards of the technology, assess it and accept it until it
This section examines a few additional scenar- can be formalized in a standard. If technology 20
ios where a regulatory professional may not utilized in a device surpasses the standard, the
find medical device standards easily. Examples manufacturer should assess the risk of incorpo-
rating it in a device under development. Factors
21
include: a keyword search yielding an unreason-
to consider in this assessment include whether
ably long list of relevant standards; an existing
standard no longer reflecting a particular the perceived state of the art truly can become 22

233
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

the new state of the art and benefits and down- •

there is doubt the revision will
sides of using the state of the art compared to become a recognized standard
the existing standard’s recommendations. If • the adoption transition period is
the existing standard also is a recognized stan- known and the adoption deadline
dard in a certain jurisdiction, the manufacturer falls after the next generation
should be ready to explain why the device does device’s planned launch
not comply with that standard. Presumably, the 3. Design to the revised standard if the
justification explains how the new technology revision has been released already, the
meets or exceeds the standard’s intent. adoption transition period is known
A regulatory professional also may find a and occurs prior to the manufacturer’s
standard has changed while a device is under planned market approval and launch
development or regulatory review. Before con- target dates.
sidering approaches, the regulatory professional
should review the standards development It is important to note the adoption transition
process. SDOs release drafts for a comment period for revised standards can vary from
period, address those comments and release jurisdiction to jurisdiction, however, generally
the final version. Upcoming revisions to widely it is published by the SDO. One example is the
used standards generally are publicized by the known and expected transition period of 0 days
SDO and industry through publications to between ISO 14971 and EN ISO 14971 in
make stakeholders aware of proposed upcoming 2012. One caveat to revisions in the US is the
changes. Since standards are subject to periodic revised version no longer may be recognized by
review and revision, it is possible for a standard a regulatory authority even if the previous ver-
to evolve into a newer version in the middle sion was an FDA-recognized standard.
of medical device development or regulatory A regulatory professional may learn a newer
review. If this occurs, the manufacturer should version of a previously utilized standard has
gather as much information as available on been released after devices already are in pro-
pending changes and determine whether there duction or commercial use. Whether subsequent
is a transition period for adopting the new revi- revisions to existing standards used in the orig-
sion and whether this is a recognized standard. inal device design process must be incorporated
This information can be used to determine the retroactively largely depends on the jurisdiction
impact on the manufacturer’s device develop- where the device currently is commercialized.
ment timeline and process. The manufacturer In the US, FDA’s Frequently Asked Questions
may choose from a few options: on Recognition of Consensus Standards state
1. Design to both the current standard changes in a recognized standard do not affect
and what the manufacturer under- a product’s clearance or approval status retroac-
stands will be the new revision, tively, so a revision is not required.
assuming provisional changes do not Finally, a manufacturer that declared con-
conflict and add significant, additional formance to a previous standard may need to
development time. modify a device. For this scenario, the regulatory
2. Design to the current standard if the professional may assume the current revision is
manufacturer believes by doing so it recognized by FDA. In determining whether
can achieve quicker market access with to comply with all parts of the revised standard,
the current device. The manufacturer the regulatory professional should consider the
then will modify its next-generation effect that the modification has on the device’s
device to meet the new revision’s safety and effectiveness. “For some types of
changes. This option is recommended changes to a device, the Agency believes that
in instances when: submission of a new 510(k) is not required
• there is uncertainty about the revi- and that reliance on existing Quality System
sion’s release date (QS) requirements (21 CFR 820) is the least

234
 Global Medical Device Regulatory Strategy

1
burdensome approach to reasonably assure the
safety and effectiveness of the changed device.”43
4. Finally, select ‘Contact details’ to locate
information for the TC/SC Secretariat
2
If the modifications significantly affect safety
and effectiveness, then a new premarket sub-
and ‘Participating Countries’ for local
country contacts. 3
mission is generally required, as well as a new
declaration of conformity, if the manufacturer Even without being a member of a national 4
choose to use one, and the new declaration of standard committee or SDO technical com-
conformity would be for the revised standard(s)
recognized by FDA. It may not be necessary for
mittee, interested regulatory professionals may
monitor developments and submit comments
5
the manufacturer to comply with all portions on draft standards, either directly or through
of the revised standard(s), but the declaration industry associations. It is possible to join SDO 6
of conformity should describe the portion(s) of email list services at no charge. As an example,
the revised standard(s) the device does not meet steps for joining the ISO newsletter are: 7
and the rationale for them. 1. Access http://www.iso.org/iso/home.
This section addressed approaches to
handling a few atypical situations where the
html
2. Scroll down to “Keep up to date with 8
regulatory professional cannot locate a set of ISO.”
relevant standards easily. In many situations, 3. Select the subscribe button to enter 9
the regulatory professional may want to follow contact information.
or become involved directly in the standards
review or development process. In addition to There are business advantages for manufacturers
10
being able to tackle atypical situations, there are that invest resources in standards’ develop-
several benefits to getting involved, which are ment work. Having early access to information 11
discussed in the next section. that could shape the market in the future and
impact device development programs provides 12
How to Get Involved awareness of standards’ development trends.
A medical device regulatory professional can
become involved in the standards development
Manufacturers can become involved by sharing
experiences and expertise, and their interests
13
or revision process by joining the working potentially can be addressed by a standard
group in which he or she is most interested. The under development or revision. Participation in 14
professional may start by exploring an SDO’s voluntary working groups provides not only a
website to understand various subcommittees’, way to add technical contributions to standards’
development but also learn other contributors’
15
technical committees’ or working groups’ objec-
tives and contacting the appropriate group.
Generally, the group secretariat (lead) and local
concerns and discuss approaches to addressing
those concerns. 16
jurisdictional member organizations or members Finally, if a US manufacturer believes it
are posted on the SDO’s website, for example: may benefit from submitting a standard for 17
1. Enter “Medical Device” and other rel- FDA recognition, it may review Federal Register
evant terms in the search box online, Notice 63 FR 9531 of 25 February 1998 for
specifications. A medical device manufacturer
18
e.g., http://www.iso.org/iso/home.htm.
interested in proposing a standard for recog-
2. Numerous standards supporting
medical device products and pro- nition would follow an established process, 19
cesses will appear as search results. including submitting: the standard title, ref-
Select ISO 10993-1:2018 Biological erence number, date, and SDO; list of device 20
Evaluation of Medical Devices—Part types to which the standard would apply; and
1: Evaluation and Testing Within a
Risk Management Process.
brief identification of the devices’ testing, per-
formance and/or any other characteristics that
21
3. The next step is to select the link to would be addressed by a declaration of confor-
TC/SC: ISO/TC 194. mity to that standard. 22

235
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

Conclusion • Clinical and Laboratory Standards Institute (CLSI)

Point-of-Care IVD Testing. https://clsi.org/. Accessed
Standards, by definition, are documents 13 July 2020.
established by consensus and approved by a • Appropriate Use of Voluntary Consensus Standards
recognized body. Medical device standards pro- in Premarket Submissions for Medical Devices:
vide for common and repeated use, guidelines Guidance for Industry and FDA Staff. FDA
website. https://www.fda.gov/regulatory-in-
or characteristics for activities or their results, formation/search-fda-guidance-documents/
aimed at achieving the optimal degree of order. appropriate-use-voluntary-consensus-standards-pre-
In the medical device global regulatory strategy market-submissions-medical-devices. Accessed 14
context, standards are considered “norms” in July 2020.
• Guidance Document. The Content of Investigational
some countries that must be followed during Device Exemption (IDE) and Premarket Approval
the conformity assessment process to meet (PMA) Applications for Artificial Pancreas
regulatory Essential Requirements. Using stan- Device Systems. Guidance for Industry and Food
dards confers a presumption of conformity with and Drug Administration Staff. FDA website.
https://www.fda.gov/regulatory-information/
mandatory regulatory requirements of these search-fda-guidance-documents/content-investiga-
countries. In other countries, standards, in the tional-device-exemption-ide-and-premarket-approv-
context of meeting regulatory requirements, are al-pma-applications-artificial. Accessed 13 July 2020.
not standalone documents and must be applied • Guidance for Industry and Food and Drug
Administration Staff. FDA website. https://www.fda.
in parallel with local regulations. Generally, gov/media/71983/download. Accessed 13 July 2020.
standards developed by SDOs are voluntary • Guidance for Industry and Food and Drug
and should be utilized in consultation with local Administration Staff: Content of Premarket
laws and IMDRF guidelines. Submissions for Management of Cybersecurity in
Medical Devices and Factors to Consider When Making
Benefit-Risk Determinations in Medical Device
Guidances, Resources and Standards
Premarket Approval and De Novo Classifications.
• AAMI ANSI HE75:2009(2013) Human Factors
FDA website. https://www.fda.gov/regulato-
Engineering—Design of Medical Devices. AAMI web-
ry-information/search-fda-guidance-documents/
site. https://my.aami.org/aamiresources/previewfiles/
content-premarket-submissions-management-cyber-
he75_1311_preview.pdf. Accessed 13 July 2020.
security-medical-devices. Accessed 13 July 2020.
• ASTM F 2516-07 Standard Test Method for Tension
• Final Guidance for Industry and the Food and
Testing of Nickel-Titanium Superelastic Materials.
Drug Administration Staff: The Content of
ASTM website. https://www.astm.org/DATABASE.
Investigational Device Exemption (IDE) and
CART/HISTORICAL/F2516-07.htm. Accessed 13
Premarket Approval (PMA) Applications for
July 2020.
Artificial Pancreas Device Systems. FDA website.
• ASTM F 1980-07(2011) Standard Guide for
https://www.fda.gov/regulatory-information/
Accelerated Aging of Sterile Barrier Systems for Medical
search-fda-guidance-documents/content-investiga-
Devices. ASTM website. https://www.astm.org/
tional-device-exemption-ide-and-premarket-approv-
DATABASE.CART/HISTORICAL/F1980-07R11.
al-pma-applications-artificial. Accessed 13 July 2020.
htm. Accessed 13 July 2020.
• Medical Device User Fee Amendments
• ASTM D 4169 Standard Practice for Performance
(MDUFA). FDA website. https://www.fda.gov/
Testing of Shipping Containers and Systems. ASTM
industry/fda-user-fee-programs/medical-device-us-
website. https://www.astm.org/Standards/D4169.htm.
er-fee-amendments-mdufa. Accessed 13 July 2020.
Accessed 13 July 2020.
• IEC 60601-1-2 Electromagnetic Disturbances:
• ASTM D 642-00 Standard Test Method for
Requirements and Tests. IEC website. https://www.
Determining Compressive Resultant of Shipping
iecee.org/dyn/www/f ?p=106:49:0::::FSP_STD_
Containers, Components and Unit Loads. ASTM
ID:2590. Accessed 13 July 2020.
website. http://materialstandard.com/wp-content/
• IEC 60601 Part 1-3: General Requirements for Basic
uploads/2019/12/D642-15.pdf. Accessed 13 July
Safety and Essential Performance: Collateral Standard:
2020.
Radiation Protection in Diagnostic X-Ray Equipment.
• The Brazil Good Manufacturing Practice (BGMP).
https://webstore.iec.ch/publication/2592. Accessed 13
ANVISA website. http://portal.anvisa.gov.br/en/com-
July 2020.
panies. Accessed 13 July 2020.
• IEC 62304 Medical Device Software—Software Life
• Medical Device Approvals in Brazil: A Review
Cycle Processes. https://webstore.iec.ch/preview/
and Update. Brazilian Resolution RDC 185/2001.
info_iec62304%7Bed1.0%7Den_d.pdf. Accessed 13
https://legacy-uploads.ul.com/wp-content/uploads/
July 2020.
sites/40/2015/02/UL_WP_Final_Medical-Device-
• IEC TR 80002-1:2009—Medical Device Software—
Approvals-in-Brazil_v7_HR.pdf. Accessed 13 July
Part 1: Guidance on the Application of ISO 14971 to
2020.

236
 Global Medical Device Regulatory Strategy

1
Medical Device Software. ISO website. https://www.iso.
org/standard/54146.html. Accessed 13 July 2020.
Management Process. ISO website. https://www.iso.
org/standard/64750.html. Accessed 13 July 2020.
2
• IEC 62 Electrical Equipment in Medical • ISO TC 210 Quality Management and Corresponding
Practice. IEC website. https://www.iec.ch/dyn/
www/f ?p=103:7:0::::FSP_ORG_ID,FSP_LANG_
General Aspects for Medical Devices. ISO website.
https://www.iso.org/committee/54892.html. Accessed
3
ID:1245,25 Accessed 13 July 2020. 13 July 2020.
• IEC SC 62A Common Aspects of Electrical Equipment
Used in Medical Practice. IEC website. https://www.
• ISO TC 212 Clinical Laboratory Testing and In Vitro
Diagnostic (IVD) Test Systems. ISO website. https://
4
iec.ch/dyn/www/f ?p=103:7:0::::FSP_ORG_ID,FSP_ www.iso.org/committee/54916.html. Accessed 13 July

•
LANG_ID:1359,25. Accessed 13 July 2020.
IEC 62366-1:2015 Medical Devices: Part 1: Application •
2020.
NEMA XR 26-2012 Access Controls for Computed
5
of Usability Engineering to Medical Devices. ISO Tomography—Identification, Interlocks and Logs.
website. https://www.iso.org/standard/63179.html.
Accessed 13 July 2020.
National Electrical Manufacturers Association
(NEMA) website. https://www.nema.org/Standards/
6
• IEEE 1012-2012 Standard for System and Software Pages/Access-Controls-for-Computed-Tomography-
Verification and Validation. IEEE website. https://
ieeexplore.ieee.org/document/6204026. Accessed 13
Identification-Interlocks-and-Logs.aspx. Accessed 13
July 2020.
7
July 2020. • NEMA MS-10-2010 Determination of Local
• BS EN 1041:2008+A1:2013 Information Supplied by
the Manufacturer of the Medical Device. https://www.
Specific Absorption Rate (SAR) in Diagnostic
Magnetic Resonance Imaging (MRI). NEMA web-
8
en-standard.eu/bs-en-1041-2008-a1-2013-informa- site. https://www.nema.org/Standards/Pages/
tion-supplied-by-the-manufacturer-of-medical-devic-
es/?gclid=Cj0KCQjw0rr4BRCtARIsAB0_48PmX-
Determination-of-Local-Specific-Absorption-Rate-
in-Diagnostic-Magnetic-Resonance-Imaging.aspx.
9
pWsIDsSqyidWyLEa_h3-p-TBBpveRMnSNR0e- Accessed 13 July 2020.
1Q7G5axP4JYXEcaAhBXEALw_wcB. Accessed 13
July 2020.
• Regulation (EU) 2017/745 of the European
Parliament and of the Council of 5 April 2017 on
10
• Essential Principles of Safety and Performance of medical devices, amending Directive 2001/83/EC,
Medical Devices and IVD Medical Devices. IMDRF
website. imdrf.org/docs/imdrf/final/technical/
Regulation (EC) No. 178/2002 and Regulation (EC)
No. 1223/2009 and repealing Council Directives
11
imdrf-tech-181031-grrp-essential-principles-n47.pdf. 90/385/EEC and 93/42/EEC (EU MDR). EUR-Lex

•
Accessed 13 July 2020.
ISO 15223-1:2016 Medical Devices: Symbols to Be Used
website. http://eur-lex.europa.eu/legal-content/EN/
TXT/?uri=CELEX%3A32017R0745. Accessed 13
12
With Medical Device Labels, Labelling and Information July 2020.
to be Supplied—Part 1: General Requirements. ISO
website. https://www.iso.org/standard/69081.html.
• Standard UL 60601-1 Medical Electrical Equipment,
Part 1: General Requirements for Safety. https://
13
Accessed 13 July 2020. standardscatalog.ul.com/ProductDetail.aspx?produc-
• ISO 14001:2015 Environmental Management Systems:
Requirements With Guidance for use. ISO website.
tId=UL60601-1. Accessed 13 July 2020. 14
https://www.iso.org/standard/60857.html. Accessed
15
References
13 July 2020. 1. ISO/IEC Directives, Part 2:2011-04, Definition 3.1.1.
• ISO 11137-3:2017 Sterilization of Health Care IEC website. https://www.iec.ch/members_experts/
Products—Radiation—Part 3: Guidance on Dosimetric
16
refdocs/iec/isoiecdir2%7Bed8.0.RLV%7Den.pdf.
Aspects of Development, Validation and Routine Control. Accessed 13 July 2020.
ISO website. https://www.iso.org/standard/63841. 2. Radio Frequency Wireless Technology in Medical
html. Accessed 13 July 2020.
17
Devices—Guidance for Industry and Food and Drug
• ISO 11607 Packaging for Terminally Sterilized Devices Administration Staff. FDA website. http://www.fda.
— Part 1: Requirements for Materials, Sterile Barrier gov/MedicalDevices/DeviceRegulationandGuidance/
Systems and Packaging Systems. ISO website. https://
www.iso.org/standard/70799.html. Accessed 13 July
2020.
GuidanceDocuments/ucm077210.htm. Accessed 13
July 2020. 18
3. Principles of Conformity Assessment for Medical Devices,
• ISO 27185:2012 Cardiac Rhythm Management
Devices—Symbols to be Used With Cardiac Rhythm
Management Device Labels and Information to be
GHTF/SG1/N78:2012. Global Harmonization Task
Force. IMDRF website. http://www.imdrf.org/docs/ 19
ghtf/final/sg1/technical-docs/ghtf-sg1-n78-2012-con-
Supplied—General Requirements. ISO website. https://
www.iso.org/standard/52552.html. Accessed 13 July
2020.
formity-assessment-medical-devices-121102.pdf.
Accessed 13 July 2020. 20
4. Danish Standards Foundation website. http://www.

21
• ISO 14155:2011 Clinical Investigation of Medical ds.dk/da. Accessed 13 July 2020.
Devices for Human Subjects—Good Clinical Practice. 5. ISO Homepage. ISO website. http://www.iso.org/iso/
ISO website. https://www.iso.org/standard/45557. home.html. Accessed 13 July 2020.

22
html. Accessed 13 July 2020. 6. ISO Members. ISO website. http://www.iso.org/
• ISO 10993 -1:2018 Biological Evaluation of Medical iso/home/about/iso_members.htm. Accessed 13 July
Devices: Part 1: Evaluation and Testing Within a Risk 2020.

237
 Chapter 15: Use of Standards in Medical Device Global Regulatory Strategy

7. International Electrotechnical Commission website. 24. Appropriate Use of Voluntary Consensus Standards in
http://www.iec.ch/. Accessed 13 July 2020. Premarket Submissions for Medical Devices. Guidance
8. CLSI Homepage. CLSI website. http://clsi.org/ for Industry and Food and Drug Administration Staff.
about-clsi/. Accessed 13 July 2020. September 2018. FDA website. https://www.fda.gov/
9. Underwriters Laboratories (UL) website. https:// regulatory-information/search-fda-guidance-docu-
ul.org/. Accessed 17 July 2020. ments/appropriate-use-voluntary-consensus-stan-
10. ANSI as American National Standards. AAMI also dards-premarket-submissions-medical-devices.
administers a number of international ISO and IEC Accessed 13 July 2020.
technical committees as well as US TAGs. 25. Accreditation Scheme for Conformity Assessment
11. ASTM International website. https://www.astm.org/ (ASCA). FDA website. https://www.fda.gov/
ABOUT/overview.html. Accessed 13 July 2020. medical-devices/standards-and-conformity-assess-
12. AHWP Homepage. AHWP website. http://www. ment-program/accreditation-scheme-conformity-as-
ahwp.info/. Accessed 13 July 2020. sessment-asca. Accessed 13 July 2020.
13. Representatives of Member Economies. AHWP 26. Guidance for Industry and Food and Drug
website. http://www.ahwp.info/index.php?q=node/80. Administration Staff. Frequently Asked Questions
Accessed 13 July 2020. on Recognition of Consensus Standards. FDA
14. GHTF Final Documents. IMDRF website. http:// website. http://www.fda.gov/MedicalDevices/
imdrf.org/documents/documents.asp#ghtf. Accessed DeviceRegulationandGuidance/GuidanceDocuments/
13 July 2020. ucm074973.htm. Accessed 13 July 2020.
15. TGA Homepage. TGA website. http://www.tga.gov. 27. Use of International Standard ISO-10993, “Biological
au/. Accessed 13 July 2020. Evaluation of Medical Devices Part 1: Evaluation and
16. ISO 13485:2003, Section 0.1 General. Medical Testing” (Replaces #G87-1 #8294) (blue book memo)
Devices—Quality Management Systems—Requirements (Text Only). FDA website. http://www.fda.gov/
for Regulatory Purposes. ISO website. http://www.iso. MedicalDevices/DeviceRegulationandGuidance/
org/iso/catalogue_detail?csnumber=36786. Accessed GuidanceDocuments/ucm080735.htm. Accessed 13
13 July 2020. July 2020.
17. “What is the relationship between FDA’s Quality 28. Code of Federal Regulations, Title 21, Part 870,
System Regulation for Devices, Part 820 and ISO Subpart D, Sec. 870.3925, Replacement heart valve.
9001: 2000?” FDA website. http://www.fda.gov/down- FDA website. https://www.accessdata.fda.gov/scripts/
loads/Medica...itySystemsRegulations/UCM134625. cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=870.3925. Accessed
pdf. Accessed 13 July 2020. 13 July 2020.
18. Quality System (QS) Regulation/Medical Device Good 29. EU Medical Devices Directive (93/42/EEC, MDD).
Manufacturing Practices. FDA website. http://www.fda. EUR-Lex website. https://eur-lex.europa.eu/le-
gov/MedicalDevices/DeviceRegulationandGuidance/ gal-content/EN/TXT/?uri=CELEX:31993L0042.
PostmarketRequirements/ Accessed 13 July 2020.
QualitySystemsRegulations/. Accessed 13 July 2020. 30. The Bjork-Shiley Convexo-Concave Heart Valve was
19. “FDA Will Transition from 21 CFR 820 QSR to removed from the US market in November 1986. See
ISO 13485:2016 for Medical Device Quality Systems also Bjork-Shiley Heart Valve Recall. Major Recalls
Audit Inspections in the Near Future.” April 2019. of Organ Replacement Devices. Brown University
Thomas Regulatory Resolutions website. https://www. website. http://biomed.brown.edu/Courses/BI108/
thomasregulatory.com/l/fda-rule-change-from-21-cfr- BI108_2007_Groups/group05/pages/bjork_shiley.
820-to-iso-13485-2016-harmonization-for-quality- html. Accessed 13 July 2020.
systems-and-audits/#. Accessed 16 July 2020. 31. Samuel FE Jr. Safe Medical Devices Act of 1990. Health
20. EN ISO 14971:2012 Medical Devices—Quality Affairs, 10, no.1 (1991):192–195. Health Affairs web-
Management Systems—Requirements for Regulatory site. http://content.healthaffairs.org/content/10/1/192.
Purposes. short. Accessed 13 July 2020.
21. IEC 62366:2014 Medical Devices—Application of 32. Draft Guidance for Industry and FDA Staff, Heart
Usability Engineering to Medical Devices. ANSI Valves—Investigational Device Exemption (IDE) and
website. http://webstore.ansi.org/RecordDetail. Premarket Approval (PMA) Applications in 1994.
aspx?sku=IEC%2062366%20Ed.%201.1%20 33. Investigational Device Exemptions (IDE’s) for Early
b:2014&source=google&adgroup=iec&gclid=C- Feasibility Medical Device Clinical Studies, Including
Ji7n6Tv-MoCFdAWHwodh3QDVA. Accessed 13 First in Human (FIH) Studies, Guidance for Industry
July 2020. and Food and Drug Administration Staff, Document
22. Standards (Medical Devices). FDA web- issued 1 October 2013. FDA website. http://www.
site. http://www.fda.gov/MedicalDevices/ fda.gov/downloads/medicaldevices/deviceregulation-
DeviceRegulationandGuidance/Standards/default. andguidance/guidancedocuments/ucm279103.pdf.
htm. Accessed 13 July 2020. Accessed 13 July 2020.
23. CDRH Standard Operating Procedures for Identification 34. ISO 5830-2:2015 Cardiovascular Implants—Cardiac
of Candidate Consensus Standards for Recognition. Valve Prostheses—Part 2: Surgically Implanted Heart
FDA website. http://www.fda.gov/MedicalDevices/ Valve Substitutes. ISO webisite. https://www.iso.org/
DeviceRegulationandGuidance/GuidanceDocuments/ standard/51314.html. Accessed 17 July 2020.
ucm077307.htm. Accessed 13 July 2020.

238
 Global Medical Device Regulatory Strategy

1
35. Cardiovascular implants—Cardiac Valve Prostheses.
ANSI/AAMI/ISO 5840:2005/(R)2010. ANSI
catalogue_detail.htm?csnumber=51313. Accessed 13
July 2020.
2
website. http://webstore.ansi.org/RecordDetail.as- 39. ISO 10555-4:1996—Sterile, single-use intravascular
px?sku=ANSI%2FAAMI%2FISO+5840%3A2005+
(R2010). Accessed 13 July 2020.
catheters—Part 4: Balloon dilatation catheters. ISO
website. http://www.iso.org/iso/catalogue_detail.
3
36. Requests for Feedback on Medical Device htm?csnumber=19056. Accessed 13 July 2020.
Submissions: The Pre-Submission Program and
Meetings with Food and Drug Administration
40. ISO 25539-2:2008—Cardiovascular implants—
Endovascular devices—Part 2: Vascular stents. ISO
4
Staff: Guidance for Industry and Food and Drug website. http://www.iso.org/iso/iso_catalogue/cata-
Administration Staff. FDA website. http://
www.fda.gov/downloads/MedicalDevices/
logue_ics/catalogue_detail_ics.htm?csnumber=35887.
Accessed 13 July 2020.
5
DeviceRegulationandGuidance/GuidanceDocuments/ 41. “FDA Insights: The ISO Standard for Endovascular
UCM311176.pdf. Accessed 13 July 2020.
37. Use of International Standard ISO-10993, “Biological
Grafts.” EndoVascular Today website. http://evtoday.
com/2003/08/0703_131.html/. Accessed 13 July 2020.
6
Evaluation of Medical Devices Part 1: Evaluation and 42. “Magnetic Needle Tackles Suturing in Challenging
Testing.” Final document issued 16 June 2016. FDA
website. https://www.fda.gov/regulatory-information/
Surgical Fields.” Boston Children’s Hospital website.
http://vector.childrenshospital.org/2014/10/mag-
7
search-fda-guidance-documents/use-internation- netic-needle-tackles-suturing-in-challenging-surgi-
al-standard-iso-10993-1-biological-evaluation-med-
ical-devices-part-1-evaluation-and. Accessed 13 July 43.
cal-fields/. Accessed 13 July 2020.
Is a new 510(k) required for a modification to
8
2020. the device? FDA website. https://www.fda.gov/
38. ISO 5840-3:2013—Cardiac valve prostheses—Part
3: Heart valve substitutes implanted by transcatheter
medical-devices/premarket-notification-510k/
new-510k-required-modification-device. Accessed 16
9
techniques. ISO website. http://www.iso.org/iso/ July 2020.
10
11
12
13
14
15
16
17
18
19
20
21
22

239